Peking Union Medical College, China.
Dr. De-Pei Liu is currently a professor of National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC). Dr. Liu graduated with a Ph.D. from CAMS & PUMC in 1986. He completed his Postdoctoral Fellowship in molecular biology at University of California, San Francisco (UCSF), and was promoted to be a Professor of CAMS & PUMC in 1992. Dr. Liu’s research expertise is molecular mechanisms of cardiovascular diseases, gene regulation and gene therapy. He has published more than 120 original research articles and invited reviews. Throughout his academic career, Dr. Liu has received numerous awards including three items of awards of Advance of Science and Technology, the Ministry of Health, P.R.China and one item of award of the National Natural Sciences Foundation. He is also serving as a member of Chinese Academy of Engineering (CAE), member of Institute of Medicine (IOM) of the National Academies and member of Third World Academy of Sciences (TWAS).
Protective roles of SIRT1 in arteriosclerotic cardiovascular disease
Cardiovascular diseases are the leading causes of death and disability in the world. A better understanding for the molecular mechanisms in the development of cardiovascular diseases will provide more strategies for their diagnosis, treatment and prevention. Sirtuin 1 (SIRT1), the closest homology to the yeast Sir2 protein in human sirtuins, has been implicated in aging, metabolism, and tolerance to oxidative stress via its ability to deacetylate a variety of substrates, including histones, transcription factors, and coregulators. The results of recent studies from our lab have demonstrated that endothelial SIRT1 is an anti-atherosclerosis factor and prevents the hyperlipidemia and hyperglycemia-induced endothelial damages. Moreover, SIRT1 acts as a novel modulator linking the coordinated responses of vascular smooth muscle cells (VSMCs) to injury. We summarized the beneficial effects of SIRT1 in vascular system and proposed that SIRT1 and its activators can become novel therapeutic targets for arteriosclerotic cardiovascular disease.
Peter Liu, M.D., FRCPC
University of Ottawa, Canada
Peter Liu is the Scientific Director/Vice President of Research of the University of Ottawa Heart Institute, and also Professor of Medicine and Physiology at the University of Toronto and University of Ottawa. He was the former Scientific Director of the Institute of Circulatory and Respiratory Health at the Canadian Institutes of Health Research. Dr. Liu graduated from the University of Toronto Faculty of Medicine. He pursued post-doctoral fellowships in cardiovascular imaging and immunology at the Massachusetts General Hospital of Harvard Medical School, and clinical epidemiology at McMaster University. At the University of Toronto, he was the Heart & Stroke/Polo Chair Professor at the University Health Network, and also the inaugural Director of the Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research at the University of Toronto.
His research focuses on the pathophysiology and clinical outcomes of heart failure from bench to bedside. His team has elucidated the role of inflammation in changing heart structure and function, and potential novel treatment targets in heart failure. His laboratory has also identified how environmental insults such as viruses and pressure load can accelerate heart failure and coronary artery disease, and is developing novel vaccines to prevent these complications. To unravel the evolution of chronic diseases, his team is also pursuing novel biomarkers and therapeutic targets for early cardiovascular disease identification and intervention. He has published over 350 peer-reviewed articles in high impact journals, and received numerous awards in recognition of his research and scientific accomplishments, including the Canadian Cardiovascular Society Research Achievement and Lifetime Achievement Awards.
Dr. Liu has chaired scientific sessions of the Canadian Cardiovascular Society, Heart Failure Society of America, the International Society of Heart Research and the Human Proteomic Organization, amongst others. Currently he is the Director of the National C-CHANGE Initiative, harmonizing and integrating cardiovascular preventive guidelines for both professionals and patients, and developing strategies for implementation. The harmonized Canadian C-CHANGE guidelines have recently been chosen by the provincial premiers in Canada as the first chronic disease guideline to be mandated by the Ministries of Health across the entire country. He is also President of the International Society of Heart Failure of the World Heart Federation (WHF), and also serves on the Research and Policy Committees of the World Heart Federation, coordinating the global fight against heart disease and promoting its prevention.
Hongliang Li, M.D., Ph.D.
Wuhan University, China
Dr. Hongliang Li is Professor of Medicine at the Wuhan University. Dr. Li currently serves as the Director of Collaborative Innovation Center of Model Animal and Vice Director of Cardiovascular Research Institute of Wuhan University. After obtaining his Ph.D. from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, he pursued his post-doctoral trainings in Joslin Diabetes Center of Harvard Medical School, and department of Cardiology at the University of Toronto. In past fifteen years, he has published over 80 peer-reviewed articles in highly impacted journals including Circulation, Circulation Research, Hepatology, Nature Communications, PNAS, Diabetes, Journal of Hepatology, Cell death & differentiation, Hypertension, and Cardiovascular Research. His research achievement is also reflected by his great success in grant application. Since 2008, he has obtained over $20 million research grants from Ministry of Science and Technology, Ministry of Education of the People’s Republic of China and National Natural Science Foundation of China. Dr. Li’s current research programs are focused on defining IRF signaling in cardiometabolic diseases. Dr. Li is also interested in the development of biotechnologies for genome manipulation, phenotypic characterization, and identification of genetic components of complex human disease. He has established a perfect platform for making transgenic and knockout animal models including mouse, rat, and rabbit. His center has offered transgenic production, gene targeting, and generation of chimeras of mice, rats and rabbits. His group has developed over 700 strains of gene knock-out and transgenic mice and 200 strains of knockout rats, all of which have been made available to Chinese scientists. His work has greatly facilitated the development of the model animals in China.
Ming-Hui Zou, M.D., Ph.D.
University of Oklahoma Health Science, USA
Dr. Zou graduated from Hubei Medical College at Xianning with a Bachelor’s degree in Medicine in 1985. He obtained his Ph.D. in France in 1994 and his Doctor of Science in 1999 in Germany. Dr. Zou became Assistant Professor at Boston University School of Medicine in 2000 and Associate Professor at University of Tennessee in 2003. Since May 2005, Dr. Zou has been appointed as Professor of Medicine, and Professor of Biochemistry and Molecular Biology at University of Oklahoma Health Science Center. He currently serves as the Chief of the section of Molecular Medicine and vice chairman for research, Department of Medicine. He also holds the Travis Endowed Chair in Endocrinology and the Warren Endowed Chair Professorship in Diabetes Research at the University of Oklahoma Health Science Center. He was awarded the George Lynn Cross Professor, the highest research honor that a faculty member may receive from the University of Oklahoma in 2013.
Dr. Zou has been productively working in the area of cardiovascular biology and diseases for 20 years. Dr. Zou’s ongoing research programs focus on the means to sense oxidative stress, reduce it, or ameliorate the body’s adverse response to it. Dr. Zou was instrumental in examining the role of nitric oxide and oxidative stress in the regulation of blood flow and vascular function. He performed elegant, state-of-the-art studies to show that the selective modification of two key proteins, prostacyclin synthase and endothelial nitric oxide synthase, is critical in the deregulation of vessel function from nitric oxide and superoxide. Dr. Zou’s group was also the first to demonstrate that the AMPK, a key enzyme in the regulation of energy metabolism, obesity, diabetes, and cardiovascular diseases, functions as a sensor and regulator of oxidative stress. Dr. Zou’s contributions in this area are significant and his work represents outstanding breakthrough research, which has been recognized by many other investigators in the fields. An independent investigator of the National Institutes of Health, the Juvenile Diabetes Research Foundation International, and the American Diabetes Association, and a National Scientist Development and National Established Investigator awardee of the American Heart Association, Dr. Zou has used these (and many other awards) to make scientific observations in fields with great potential for immediately clinical relevance. Since 2005, Dr. Zou has served on several national study panels such as the National Institutes of Health, American Heart Association, and American Diabetes Association and on many international panels including the National Science Foundation of China, the Research Grant Council and the University of Grant Committee of Hong Kong, the Wellcome Trust of England, and German Science Foundation (DFG). He is also the Editor-in-chief for the journals “Diabetes, Metabolic Syndrome and Obesity” “World Journal of Diabetes” and has served the editorial boards of many prestigious journals including J. Clin. Invest., Circulation、Circulation Research, ATVB, Diabetes, etc. In past three years, he has published over 50 peer reviewed papers in highly impacted journals including Nature Medicine, J. Clin. Invest., Circulation, Circulation Research, Diabetes, Mol. Cell. Biol. Atherosclerosis, Vascular Biology, and Thrombosis, J. Biol. Chem., Hypertension. In 2008 he was elected to the American Society for Clinical Investigation, one of the United States’ oldest honor societies of physician-scientists, membership in which reflects accomplishments by its members at an early stage (<45 years old) in their careers.
Promotion of Rab7-mediated lysosome-dependent neuropilin-1 degradation by LKB1 inhibits angiogenesis in vivo
Internalized transmembrane receptors (TMRs) are typically recycled back to the cell-surface or targeted to degradation pathways. Efficient trafficking of TMRs is critical to the regulation of several processes, including signal transduction pathways, development and disease. Here, we identify novel trafficking of an angiogenic receptor, neuropilin-1 (NRP-1) by liver kinase B1 (LKB1), a serine-threonine protein kinase of the calcium calmodulin family. Aberrant NRP-1 expression in tumor cells make the receptor an attractive therapeutic target.
Mechanistically, we found that LKB1 accentuates complex formation of NRP-1 with Rab7 endosomes. LKB1 specifically binds GTP-bound Rab7 (Rab7-Q67L) but not dominant-negative Rab7-T22N (GDP-bound) constructs, promoting rapid transfer and lysosome degradation of NRP-1. Rab7 depletion (siRNA) disrupts NRP-1 transfer to the lysosome, resulting in recovery of the receptor, and increased tumor growth and angiogenesis.
Our findings suggest that LKB1 functions as a Rab7 effector, and suppresses angiogenesis by promoting the cellular trafficking of NRP-1 from Rab7 vesicles to the lysosome for degradation.
Xinliang Ma, M.D., Ph.D., FAHA
Thomas Jefferson University, USA
Dr. Ma received his M.D. degree in 1982 (Shanxi Medical University, China) and Ph.D. degree in 1988 (Fourth Military Medical University, China). Following his postdoctoral training from 1989 to 2002 in Department of Physiology at Thomas Jefferson University, he was recruited to the Department of Surgery as an Assistant Professor in 1993. He was promoted to Associate Professor in 1997 and Professor in 2002. He is currently a Tenured Professor at Thomas Jefferson University, Philadelphia and serves as the Director of Cardiovascular Research Program in Department of Emergency Medicine. He has published more than 200 scientific research papers in peer-reviewed journals including Journal of Clinical Investigation, PNAS, Circulation and Circulation Research. His works have been cited by other investigators in the field for more than 11,000 times. He has been a member of study section for NIH, American Heart Association and American Diabetes Association. His research projects have been continually supported by NIH, ADA and AHA since 1999. He is an editorial member of Circulation Research and American Journal of Physiology. He is interested in identifying the signaling mechanisms responsible for post-ischemic myocardial apoptosis with special emphasis on oxidative/nitrative stress and post-translational protein modification.
Systemic Adiponectin Mulfunction and Diabetic Cardiovascular Injury
Adiponectin (Ad) is an abundant protein hormone regulatory of numerous metabolic processes. The 30kDa protein mainly originates from adipose tissue, with both full length and globular domain forms existent in the bloodstream. A collagenous region within adiponectin leads to its spontaneous self assemblage into various oligomeric isoforms, including trimers, hexamers, and high molecular weight multimers. Two membrane-spanning receptors for adiponectin have been identified, with differing concentration distribution in various body tissues. The major intracellular pathway activated by adiponectin includes phosphorylation of AMP-activated protein kinase, responsible for many of adiponectin’s downstream actions, including increased glucose utilization, fatty acid oxidation, increased muscle glucose uptake, and decreased liver gluconeogenesis.
Since its discovery in 1995, adiponectin has garnered great attention for its role in diabetes and cardiovascular pathology. Clinical observations have demonstrated the association of hypoadiponectinemia in patients with obesity, cardiovascular disease, insulin resistance, diabetes, and the metabolic syndrome. In this presentation, I shall elaborate currently known information about adiponectin deficiency in relationship to diabetes, cardiovascular disease (including atherosclerosis, endothelial dysfunction, lipid metabolism, and myocardium), and other body system disorders (including the immune, liver, pulmonary, renal, and oncologic systems), and finally provide perspective about the future of adiponectin research and its potential therapeutic benefits.
Yun Zhang, M.D., Ph.D., FACC, FESC
Shandong University, China
Dr. Yun Zhang graduated from Shandong Medical College in 1976 and received his Master of Medicine degree from Shandong Medical College in 1981 and his Ph.D. degree from University of Oslo, Norway in 1985. Dr. Zhang is currently Professor of Medicine, Chairman of Department of Cardiology, Shandong University Qilu Hospital, Director of the Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health and President of Cheeloo Health Science Center, Shandong University. He serves as a member of the international editorial board of Nature Review Cardiology, JACC Cardiovascular Imaging, Heart, Clinical and Experimental Pharmacology and Physiology, and Science in China Series C-Life Sciences. He serves as Editor in Chief of Chinese Journal of Ultrasonography and Associate Editor of Chinese Journal of Cardiology. He is the current President of Chinese Society of Ultrasound in Medicine, President of the Chinese Society of Echocardiography, Vice President of the Chinese Society of Cardiology and Vice President of the Chinese College of Cardiovascular Physician. Dr. Zhang is a pioneer of stress echocardiography, Doppler echocardiography, multiplane transesophageal echocardiography and three-dimensional echocardiography in China. As a principal investigator, he has led more than 50 research projects in the field of arteriosclerosis and heart failure. He has authored more than 900 research papers in peer-reviewed journals, such as Lancet, Nat Med, Cell Metab, Proc Natl Acad Sci USA, J Am Coll Cardiol, Eur Heart J, Circ Res, Diabetes, Autophagy and Arterioscler Thromb Vasc Biol, and 34 textbooks in cardiovascular medicine. He has been awarded 4 state prizes and 48 ministerial or provincial prizes for Scientific and Technological Progress and received more than 20 international and national honorary awards. He was elected a Member of Chinese Academy of Engineering in 2001, Fellow of American College of Cardiology (FACC) in 2008, Fellow of European Society of Cardiology (FESC) in 2012 and Honorary Fellow of the American Society of Echocardiography (HFASE) in 2013.
Yaling Han, M.D., Ph.D., FACC
General Hospital of Shenyang Military Region, China
Professor Ya-Ling Han, a member of Chinese Academy of engineering, is a senior and experienced cardiologist in China. She devoted to the innovation in cardiovascular intervention for 20 years. From early stage of 21th, she created “modified tiny crush stent technology” and “multi-wire plaque crushing technology” and first started the high dose clopidogrel, triple antiplatelet therapy (aspirin+clopidogrel+cilostazol) and individualized antiplatelet strategy for Chinese acute coronary syndrome patients. She took charge in many large scale clinical studies such as the CREATE study (JACC INT2009), the TRACK-D study(JACC2014),the BRIGHT study(TCT2014). By the supporting of key project of national natural science foundation and other 8 items of Natural Science Foundation, Professor Han’s team studied the biological roles of CREG gene, which achieved lots in academics. Professor Han has been recognized by medical and public community with a number of awards for her outstanding clinical, teaching, scientific and social service. As the first author, she had obtained two items of “Second Class Prize of National Scientific And Technological Progress” in 2008 and 2013 respectively, and “Asian Pacific Academic Opinion Leader Award” in 2013. Meanwhile, she is the vice President of Chinese Society of Cardiology, the President elect of Chinese College of Cardiovascular Physicians of Chinese Medical Doctor Association, the vice Chief Editor of Chinese Journal of Cardiology, FACC, FESC, and the Associate Editor of Cardiovascular Therapeutics.
Congxin Huang, Ph.D.
Wuhan University, China
Dr. Congxin Huang is currently a Professor of Cardiology at the Renmin Hospital of Wuhan University. He is the Director of the Cardiovascular Research Institute of Wuhan University and the Hubei Provincial Key Laboratory of Cardiovascular Disease. Dr. Huang is currently the President of the Chinese Society of Pacing and Electrophysiology and the Vice President of the National Cardiovascular Disease Expert Committee. His academic and research interests include interventional cardiology, ventricular arrhythmia in heart failure and myocardial infarction, mechanism and management of atrial fibrillation. Dr. Huang has received over 20 scientific awards in his research field, of which 3 were rated the second grade award of National Progresses of Science and Technology, and 6 the first grade award of Progresses of Science and Technology of Hubei province. He is currently the Editor-in-Chief of the Chinese Journal of Cardiac Pacing and Electrophysiology and the Medical Journal of Wuhan University. He is also the Vice Editor-in-Chief of the Chinese Journal of Cardiac Arrhythmias and the Journal of Cardiovascular Electrophysiology (Chinese edition). Dr. Huang has published over 400 peer-reviewed manuscripts in scientific journals, including PNAS, Int J Cardiol, PLoS One, EuroIntervention, JCE and Europace. He is currently serving as principal investigator for several multi-center clinical trials. Dr. Huang is a fellow of the Heart Rhythm Society, the European Heart Rhythm Association, the European Society of Cardiology and the American College of Cardiology. He is also a member of Executive Committee of the Asia Pacific Heart Rhythm Society.
Qizhu Tang, M.D., Ph.D.
Wuhan University, China
Dr. Qizhu Tang is currently a President of Renmin Hospital of Wuhan University and Professor of Cardiology Department in Wuhan University. Dr. Tang received his Ph.D. in cardiology from Wuhan University in 2003. Dr. Tang’s expertise includes the prevention and treatment of myocardial remodeling, by building knockout and transgenic mice and rats to explore the mechanism and pathological features, and various arrhythmias diseases. Dr. Tang started medical treatment career as well as teaching and researching since July, 1987. By now, he has published over 180 articles in major journals both domestically and abroad, 54 articles of which have been in the SCI database. In addition, Dr. Tang published 19 works of academic monograph and led 14projects of National Natural Science Fond, Expansion Platform Constructure Project of the Education Minstry and Hubei Major Science and Technology Project, etc. Dr. Tang was awarded with the “May 4th Youth Medal of Hubei province” in 2001, “Youth Science and Technology Medal” in 2002, “Special Government Allowance From The State Council” in 2004, “May 1st Labor Medal of Hubei Province” in 2008, “National May 1st Medal” in 2011 and “Outstanding Contribution Yong and Middle-Aged Expert of Ministry of Health of PRC” in 2012. He currently serves in the editorial board of Chinese Journal of Cardiac Pacing and Electrophysiology, Chinese Journal of Pharmacoepidemiology, World Clinical Drugs, Journal of Clinical Internal Medicine and China Medicine. He is a council member for Chinese Biomedical Engineering, Cardiology Department of Chinese Medical Doctor Association and Heart Failure Department of Chinese Medical Association, and the Director of Hubei Province of Chinese Biomedical Engineering.
Hong Jiang, M.D., Ph.D.
Wuhan University, China
Dr. Hong Jiang is currently the director of the Department of Cardiology and the Department of Internal Medicine, Renmin Hospital of Wuhan University. He is the member of the Standing Committee of Chinese society of pacing and electrophysiology and Chinese society of Biomedical Engineering Heart Rhythm Society. He is also the Vice Chair of Hubei Medical Association. Dr. Jiang received his Ph.D. and M.D. training in internal medicine in Wuhan University. His expertise includes cardiac electrophysiology, atherosclerosis and hypertension. Dr. Jiang received China national science and technology progress awards in 2001, 2004 and 2011, Hubei province national science and technology progress award in 2010, the Fifteenth Sackler Chinese physicians Annual Awards in 1999. He currently serves as the associate chief editor of Chinese Journal of Cardiac pacing and electrophysiology, editorial member of Chinese Journal of Cardiac Arrhythmias. Dr. Jiang has published over 80 peer-reviewed manuscripts in many top ranked scientific journals, including Cardiovascular Research, International Journal of Cardiology, Journal of Cardiovascular Electrophysiology. Dr. Jiang is currently serving as principal investigator for several grants including National Natural Science foundation of China.
Mukesh K. Jain, M.D.
Case Western Reserve University, USA
Dr. Jain is the Ellery Sedgwick Jr. Chair & Distinguished Scientist; Director, Case Cardiovascular Research Institute and Professor of Medicine, Case Western Reserve University School of Medicine; Scientific Director, Harrington Discovery Institute and Chief Research Officer, Harrington Heart & Vascular Institute at University Hospitals Case Medical Center.
Dr. Jain is recognized for discovery of essential roles for the transcription factor family Krüppel-like factors (KLFs) in inflammation and metabolism. In addition, he has translated this corpus of work into animals and humans, thus implicating KLFs in the physiology of inflammatory and metabolic diseases including sepsis, myopathy, diabetes, and vascular dysfunction. As a direct result of this work, KLFs are now increasingly viewed, together with classic regulators such as NFkB and nuclear receptors, as nodal determinants of cellular inflammation and metabolism.
Dr. Jain’s clinical and academic contributions are recognized by numerous awards and honors including election to the American Society for Clinical Investigation (ASCI), Association of American Physicians (AAP), and Association of University Cardiologists (AUC). Dr. Jain is a member of the American Heart Association’s Advancement of Science and Basic Science Council, serves on multiple editorial boards, and has been the recipient of numerous NIH grants.
Dr. Jain received his M.D. from the University of Buffalo School of Medicine. He completed his residency in internal medicine at the Beth Israel Hospital in Boston and completed a cardiovascular medicine fellowship at Brigham & Women’s Hospital, Harvard Medical School.
Novel insights into cardio-metabolic disease
Our laboratory has identified key regulatory roles for KLFs in cardiovascular biology, metabolism, and innate immunity. Aspects of this work will be discussed. These discoveries have opened new areas of investigation and contributed to growing appreciation that KLFs are master regulators of cellular homeostasis and tissue function.
Kenneth Walsh, Ph.D.
Boston University School of Medicine, USA
Research in the Walsh laboratory is focused in a number of related areas. A major project investigates the signaling- and transcriptional-regulatory mechanisms that control both normal and pathological tissue growth in the cardiovascular system. Many of these studies involve analyses of the PI3-kinase/Akt/GSK/Forkhead signaling axis. This pathway is of critical importance in the regulation of organ growth and body size. Signaling through this pathway controls cellular enlargement (hypertrophy), cell death (apoptosis), and blood vessel recruitment and growth (angiogenesis). We have shown that the PI3-kinase/Akt/GSK/Forkhead signaling axis regulates multiple steps critical in angiogenesis including endothelial cell apoptosis, differentiation, nitric oxide production and migration. We have also shown that some of these signaling steps are important for cardiac hypertrophy during normal postnatal development, and that they regulate myocyte survival in models of heart disease. Using mouse genetic models that alter the expression of Akt in cardiac cells, we have found that perturbations in crosstalk mechanisms between cardiac myocytes and vascular endothelial cells contribute to the transitions from compensated hypertrophy to heart failure. Factors involved in this regulation include VEGF, Fstl1, Fstl3 and Activin-A. Subsequent studies in patient populations have shown that at least one of these factors (Fstl1) is upregulated in clinical heart failure and is predictive of mortality in patients with acute coronary syndrome.
Related studies examine how alterations in the expression of adipocyte-derived cytokines, referred to as adipokines, interfere with normal signaling within the cardiovascular system and thereby contribute to cardiovascular disease. Adiponectin is an anti-inflammatory adipokine that is down-regulated in obesity. Studies by the Walsh laboratory were first to show that adiponectin directly acts on the heart and vasculature as a cardio-protective factor. Recently this laboratory found that the Sfrp5/Wnt5a regulatory axis functions to control systemic metabolism through regulation of adipose tissue inflammation. Finally, the Walsh lab is examining how age-associated loss of skeletal muscle mass affects metabolic and cardiovascular function, and is exploring the possibility that muscle-secreted factors (myokines) confer some of the benefits of exercise training on cardiovascular and metabolic diseases.
Mechanisms of obesity-linked cardiovascular disease
It is widely recognized that adipose tissue functions as an endocrine organ and that obesity contributes to metabolic and cardiovascular disorders through the development of a chronic inflammatory state that results from alterations in the levels of adipocyte-derived cytokines (adipokines). Most adipokines are pro-inflammatory and thereby promote metabolic and cardiovascular diseases, but a small number of anti-inflammatory adipokines have been also been identified. To better understand the interplay between body composition and cardiovascular disease, we have devised methods to isolate novel adipokine candidates with pro- and anti-inflammatory properties. Some of these studies have shown that regulation of non-canonical Wnt signaling contributes to obesity-associated metabolic dysfunction by modulating adipose tissue JNK signaling and inflammation. In metabolically normal mice (fed standard chow diets), it can be shown that these same regulatory pathways control pathological processes in heart and blood vessels, thereby providing new mechanistic links between cardiovascular disease and dysregulated adipokine expression in obesity.
Keith A. A. Fox, M.B.
University of Edinburgh, UK
Professor Keith Fox, BSc (hons) MBChB, FRCP, FESC, FACC, FMedSci: the British Heart Foundation and the Duke of Edinburgh Professor of Cardiology of the University of Edinburgh 1989-2013.
He was a founding fellow of the European Society of Cardiology and is currently Chair of the Programme of the European Society of Cardiology. In addition, he was President of the British Cardiovascular Society from 2009 to 2012. Professor Fox gave the State-of-the-Art Lecture on Acute Coronary Syndromes at the American Heart Association as well as the 2009 Plenary Lecture at the European Society of Cardiology-American College of Cardiology Symposium, and the Lord Rayner Lecture of the Royal College of Physicians29-10-12(London) and the Sir Stanley Davidson Lecture of the Royal College (Edinburgh) 15-11-12 and the Michael Davies Memorial Lecture (London) 09-12-13. His awards include the Silver Medal of the European Society of Cardiology in 2010.
Professor Fox’s major research interest lies in the mechanisms and manifestations of acute coronary arterial disease; his work extends from underlying biological mechanisms to in vitro and in vivo studies and clinical trials. He is the author of more than 608 scientific papers (H index Web of Science 82, Citations: 36,139 to December 2013).
Professor Fox is chairman of the RITA programme, co-chairman of ROCKET-AF, and OASIS programme and chair of the GRACE programme (the largest multinational study in acute coronary syndromes), and a lead investigator for studies on novel anti-thrombins, anti-coagulants and antiplatelets.
He is an International Associate Editor of the European Heart Journal and a member of the editorial boards of a number of journals. He is President of Action on Smoking and Health (ASH Scotland). His ongoing research interests include the mechanisms of inflammation and plaque rupture in acute coronary syndromes and antithrombotic therapies.
Acute Coronary Syndromes and Atherogenesis: the future?
Within the field of acute coronary artery disease most attention has focussed on acute manifestations of myocardial infarction and early management. However, the frequency of recurrent and multiple plaque rupture events has been under-recognised and the impact under-estimated. Increasing evidence demonstrates that those ACS patients that survive to hospital discharge have a higher risk of recurrent cardiovascular events having presented with a non ST elevation ACS compared with ST elevation infarction (K A A Fox et al Nature CV Med). Angiographic studies, intravascular ultrasound and optical imaging all suggest that plaque rupture related events are multi-focal. Phenotypic characterisation can help in predicting future cardiovascular outcome after presentation with ACS, including the use of risk scores (Fox et al BMJ 2006, 2014). However, the predictive accuracy for recurrent plaque rupture is relatively poor (C statistic 0.65) and novel studies are investigating whether genotype and RNA expression analyses are associated with up-regulation of specific inflammatory pathways. The aim is to provide mechanistic insights into the identification of individuals at high risk of recurrent plaque rupture and to modulate these pathways and modify outcome. A key goal is to identify “vulnerable” plaques prior to clinically manifest rupture and thrombosis. Novel ex-vivo optical imaging approaches (optical projection tomography) utilize laser light with exquisite resolution of the vascular wall, permitting imaging of fluorescent probes of interest, and 2D or 3D reconstruction. In addition using a combined 18F NaF PET and CT imaging technique pioneered in Edinburgh (Circulation. 2012; 125(1):76-86 and Journal American College Cardiology. 2012; 59:1539-48), we have been able to image micro-calcification at sites of unstable coronary and carotid plaques. This non-invasive approach has the potential to investigate inflammatory pathways implicated in plaque rupture and to study novel probes to modify future plaque rupture events. Although much has been achieved in the acute management of patients with ACS, there is great potential to understand and to modify susceptibility to future plaque rupture events.
William M. Chilian, Ph.D.
Northeastern Ohio Medical University, USA
Dr. William M. Chilian is the Chair and Professor of the Department of Integrative Medical Sciences at Northeastern Ohio Medical University. Dr. Chilian also is an adjunct Professor in the Department of Chemical and Biomolecular Engineering at the University of Akron and is a member of the graduate faculty of the Kent State University Biomedical Science program. Dr. Chilian previously held positions at Louisiana State University Medical School, Medical College of Wisconsin, and Texas A&M University College of Medicine. Dr. Chilian received his Ph.D. from the University of Missouri and completed his postdoctoral training at the University of Iowa. He has been the Principal Investigator on NIH grants since 1983 and currently holds two RO1 grants from the NIH. Dr. Chilian has over 140 peer-reviewed publications, and has an H-factor of 60. Dr. Chilian has been the recipient of the Distinguished Service Award from the American Heart Association for his work on the Committee for Scientific Sessions Programming, and has also been awarded the Carl J. Wiggers Award from the Cardiovascular Section of the American Physiological Society, the Robert M. Berne Award from the American Physiological Society, the Eugene M. Landis Award from the Microcirculatory Society, and the Konrad Witzig Award from the Cardiac Dynamics Society. Dr. Chilian currently serves as an Associate Editor for Circulation Research, and previously was a Guest Editor for Circulation, and was an Associate Editor for the American Journal of Physiology: Heart and Circulatory Physiology. Dr. Chilian serves on the editorial boards of Circulation; Arteriosclerosis, Thrombosis and Vascular Biology; and Basic Research in Cardiology. He also has served the NIH as an ad hoc reviewer for numerous Special Emphasis Panels, and as regular member of the Myocardial Ischemia and Metabolism study section, where he also served as Chair. Dr. Chilian is a member of the American Heart Association, where he also has the honor of being named a Fellow of the American Heart Association. He also is a member of the Microcirculatory Society, the American Physiological Society, and the American Society for Pharmacology and Experimental Therapeutics.
A New Paradigm for Heart Failure: Blunted Communication Between Cardiac Myocytes and the Coronary Vasculature
Under normal, physiological conditions, dynamic changes in cardiac work are met with an appropriate change in coronary blood flow. If cardiac work increases, as during exercise, then coronary blood flow rises appropriately. When the exercise is stopped and cardiac work decreases, blood flow to the myocardium falls. This matching of coronary blood flow to cardiac work is termed metabolic dilation. We have reported previously that coronary metabolic dilation is, at least in part, due to the mitochondrial production of H2O2, which is a feed-forward dilator. In this regard, the production of H2O2 is directly linked to metabolism and there is no feedback signal. During increases in cardiac work and myocardial oxygen consumption, the levels of H2O2 rise in the cardiac interstitium concomitantly with increases in myocardial blood flow. The mechanism of dilation by H2O2 is due to the opening of voltage-gated potassium channels (Kv channels), which would produce membrane hyperpolarization and decrease Ca++ levels in smooth muscle. H2O2 likely causes the change in Kv channel activity via redox-dependent reactions, since dilation to this oxidant is blocked by reducing agents such as diothiothreitol. It is important to note that the Kv channel family is very large with 12 families of channels. To understand which Kv channels are receptive to H2O2, we studied mice null for specific members of the Kv1 family, which are known to be redox sensitive. Mice null for Kv1.5 channels (Kv1.5-/-) show impaired metabolic dilation during increases in cardiac work; in fact, during large increases in work, the mice show signs of myocardial ischemia. If a high level of cardiac work is imposed chronically (hypertension), then the Kv1.5-/- mice develop heart failure characterized by poor pump function, high mortality and pulmonary edema. Thus, mice with impairments in coronary metabolic dilation can develop heart failure with a chronic metabolic stress. In conclusion, metabolic dilation in the heart, the coupling between metabolism and flow, is critical for proper cardiac function during changes in work. Disruption in this coupling can lead to impairments in perfusion and heart failure.
Norbert Hubner, Ph.D.
Max-Delbrück-Center for Molecular Medicine, Germany
Dr. Norbert Hubner is professor and chair in Cardiovascular and Metabolic Sciences at the Charite Medical School Berlin and head of a senior research group at the Max-Delbrück-Center for Molecular Medicine (MDC). He studied Medicine in Heidelberg and Berlin, Germany and carried out his doctoral thesis work at Children's Hospital in Boston before joining the Ganten laboratory at the MDC as postdoctoral fellow. After his postdoc he started his own research group at the MDC where he stayed since. The group's main objective is to identify the molecular basis of common genetically complex human cardiovascular and metabolic diseases. He coordinates a large EU-funded systems biology programme in the rat (EURATRANS) involving 16 institutions across Europe, Japan and the US. From March until August 2014 he was the Lee Kong Chian Centennial Professor in Cardiovascular Research at the Duke-NUS Graduate Medical School in Singapore.
Post-transcriptional regulation in heart failure
- the role of the alternative splicing factor RBM20
The RNA-binding protein RBM20 has been implicated in dilated cardiomyopathy (DCM), a major cause of chronic heart failure. To determine how RBM20 regulates alternative splicing, we combined transcriptome-wide CLIP-seq, RNA-seq, and quantitative proteomics in cell culture, rat, and human hearts. Our analyses revealed a distinct RBM20 RNA-recognition element in predominantly intronic binding sites and linked repression of exon splicing with RBM20-binding near 3’- and 5’-splice sites. Our proteomic data show RBM20 interaction with U1- and U2-snRNPs and suggests splicing repression through spliceosome stalling at complex A. Among direct RBM20 targets are several genes involved in DCM as well as new genes not previously associated with the disease process. In human failing hearts, we demonstrate that reduced expression levels of RBM20 affect alternative splicing of several direct targets, indicating that differences in RBM20 gene expression may affect cardiac function. These findings reveal a new mechanism to understand the pathogenesis of human heart failure.
Hui-Hua Li, M.D.,Ph.D.
Capital Medical University,China
Dr. Hui-Hua Li, born in October 1965. Ph.D. supervisor. Yangtze River Scholars Distinguished Professor of Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University. Winner of the National Science Foundation for Outstanding Young Scientists of China. He received his M.D. from Peking Union medical College in Pathology. He has investigated the role of ubiquitin-proteasome system and inflammation in the development of cardiomyopathy, cardiac infarction, and heart failure, etc for over ten years. He found the E3 liagses, including atrogin-1, MurF1, Nrdp1 and CHIP significantly regulated the cardiac hypertrophy, cardiomyocyte apoptosis, and cardiac contractile function through multiple signaling pathways, such as PI3K/AKT/FOXOs, ERK, calcineurin, and p53. He also revealed that DCs, NKT, macrophages and CXCR2 play a critical role in cardiac fibrosis and heart failure. Until now, he has published over 60 research papers on JCI, PNAS, Circ. Res., etc, that are cited over 2500 times in the past several years.
Randy Scott Levinson, Ph.D.
As an undergraduate student at Caltech, Randy Levinson studied the evolution and the proteolytic regulation of Alphavirus replication in the lab of James Strauss. He went on to graduate school in Keith Yamamoto's lab at the University of California, San Francisco, to study the regulation of nuclear hormone receptor signaling using a yeast genetic screen. After graduation, he carried out postdoctoral work with Eseng Lai at Memorial Sloan-Kettering Cancer Center where he investigated the role of renal stroma in embryonic kidney development. He continued these studies during a second postdoc at Columbia University with Cathy Mendelsohn before joining Nature Medicine in 2005.
Navigating the Publishing Process at High-Impact Journals
In my talk I will focus on three areas. I will briefly cover my personal research experience, the organization of our publishing house and how Nature Medicine fits within its structure, and the criteria by which we evaluate papers. The majority of the presentation will be focused on this last topic. In particular, I will cover our editorial criteria, while going over specific examples of papers we have published (and why) but also papers we considered but eventually decided to not send out for external review (and why). Hopefully this will give the audience a better feel of how editors at top research journals handle their papers. I will end the talk by also giving advice on how to approach research projects and what to highlight in the resulting papers.
Yutian Wang, Ph.D.
University of British Columbia, Canada
Dr. Yu Tian Wang, Professor and the holder of the Heart and Stroke Foundation of B.C. & Yukon Chair in Stroke Research in the Department of Medicine and the Brain Research Centre at the University of British Columbia, obtained his Ph.D. in Neuroscience in 1992 from Memorial University, Canada and both B.M. (Medicine) in 1982 and M.Sc. (Physiology) in 1985 from Shandong University Medical School in China. He worked in Department of Laboratory Medicine and Pathobiology at University of Toronto as an Assistant Professor, and then an Associate Professor between 1994 and 2001. He was also a Howard Hughes Medical Institute International Scholar between 2001-2011 and has been a Fellow of the Academy of Sciences of Royal Society of Canada since 2006. Dr. Wang’s research focuses on understanding the molecular mechanisms responsible for regulating the function and intracellular trafficking of glutamate and GABA receptors in brain function and dysfunction.
Peptide-mediated knockdown of endogenous proteins
-research tools and therapeutic potentials in vascular diseases
Rapid and reversible methods for altering the expression level of endogenous proteins are not only indispensable tools for studying complex biological systems, but may potentially drive the development of new therapeutics for the treatment of many diseases. Techniques that manipulate protein expression and function by targeting DNA or mRNA have proven to be powerful tools, but are often plagued by problems such as lack of specificity, speed, and tunability. Furthermore, their therapeutic use in treating human diseases is hindered by the lack of an efficient systemic delivery system. Here, we describe a membrane-permeable and systemically applicable targeting-peptide method that can rapidly and reversibly knockdown endogenous proteins by directing them to the lysosomes for degradation. The proposed targeting peptide consists of three domains: the cell membrane penetrating domain that can deliver the peptide across the plasma membrane and the blood brain barrier; the protein binding domain that can specifically recognize and bind to the target protein; and the lysosomal targeting signal that can deliver the peptide-protein complex into the lysosome for degradation of the target protein. Using this method, we designed a targeting peptide that could rapidly knock down death associated protein kinase 1 (DAPK1), a serine and threonine kinase that is known to mediate ischemic cell injuries in vascular diseases such as stroke or heart attack. We showed that it specifically reduced the expression levels of the active DAPK1 both in cell cultures and in intact animals. More significantly, we found that in rat models of stroke or ischemic heart attack, systemic application of the DAPK1-targeting peptide not only efficiently knocked down DAPK1 in the ischemic region, but also significantly reduced cell damage. Thus, we present a novel peptide-based method that can rapidly and reversibly knockdown endogenous proteins in situ. It is suitable for both in vitro and in vivo use, can be easily generalized to potentially degrade any protein of interest and offers a complementary approach to current genetic and chemical means of regulating the expression levels of native proteins. It may soon be proven as not only a powerful tool for scientific research, but also a means of facilitating the development of effective therapeutics for treating various human diseases.
Rama Natarajan, Ph.D., FAHA, FASN
Beckman Research Institute of City of Hope, Cannada
Dr. Rama Natarajan is currently an Endowed Professor and Director, Division of Molecular Diabetes Research, Department of Diabetes, at the Beckman Research Institute of City of Hope, Los Angeles, California. She is well known for her research pertaining to the molecular mechanisms responsible for the accelerated cardiovascular and renal complications of diabetes with over 160 publications. Her interests are to examine how diabetic conditions augment inflammatory and other pathological genes under diabetic conditions in target cells, and in animal and clinical models of diabetic vascular complications. Her laboratory was one of the first to demonstrate the role of epigenetics in diabetic vascular inflammation, and in the metabolic memory phenomenon. In addition, her laboratory was also the first to demonstrate new roles for microRNAs in regulating pro-fibrotic genes in kidney cells related to the pathogenesis of diabetic nephropathy. She is funded by grants from the National Institutes of Health (NIH) (NHLBI and NIDDK), and the Juvenile Diabetes Research Foundation (JDRF). She serves on the peer review committees of the NIH and JDRF. Dr. Natarajan is also very active in teaching, mentoring and training graduate students, fellows and faculty. She has served in the American Heart Association Council Leadership Committees and other National and International committees. She has received multiple awards and recognitions including “Scientist of the Year (2008, Beckman Res Inst) and Mentor of Women (2011, American Heart Association, ATVB Council) and delivered several endowed lectures. She is on the Editorial Boards of various journals including Diabetes, Kidney International, ATVB (Atherosclerosis, Thrombosis and Vascular Biology), and the American Journal of Physiology (Renal).
The Role of Epigenetics and microRNAs in Diabetes Vascular Complications
Diabetes is associated with significantly accelerated rates of inflammation and multiple macro- and micro-vascular complications such as atherosclerosis and nephropathy. Abnormal activation of vascular smooth muscle cells, circulating monocytes and renal cells triggered by inflammatory and fibrotic genes has been implicated, but the underlying molecular mechanisms are not fully understood. We have examined the role of epigenetic mechanisms and non-coding RNAs in the pathology of vascular complications of diabetes.
Increasing evidence suggests that epigenetic factors may modulate the complex interplay between genes and the environment and their dysregulation can contribute to human diseases such as diabetes and its complications. Epigenetics refers to changes in gene expression and phenotype that occur without actual changes in the underlying DNA sequence. Epigenetic changes, including histone post-translational modifications and DNA cytosine methylation, can affect chromatin structure and gene expression, and hence disease states. We observed that variations in key chromatin histone modifications are involved in the expression of inflammatory chemokines and cytokines in vascular smooth muscle cells and monocytes under diabetic conditions in vitro, and in cells from diabetic mice, as well as in blood cells isolated from diabetic patients relative to corresponding controls. We have also examined the role of epigenetic mechanisms in the regulation of extracellular matrix and profibrotic genes in kidney mesangial cells related to the pathogenesis of diabetic nephropathy. Non-coding RNAs like microRNAs can regulate gene expression via posttranscriptional mechanisms and are also part of the epigenetic layer. Our laboratory has identified a cross-talk between microRNAs and the epigenetic machinery in the regulation of inflammatory and pro-fibrotic genes under diabetic conditions. We are performing epigenome profiling and implementing bio-informatics and systems biology approaches to identify diabetes-specific epigenetic signatures genome-wide in cultured cells, and in cells from type 1 diabetic versus non-diabetic subjects. Furthermore, we are also examining whether key variations in the epigenome may be responsible for the phenomenon of metabolic memory. Together, our studies suggest that epigenetic factors and key microRNAs play modulatory and fine-tuning roles in the development of diabetic vascular complications. They could lead to the development of much needed new therapies for the sustained and debilitating vascular complications of diabetes.
Xudong Liao, Ph.D.
Case Western Reserve University School of Medicine, USA
Dr. Liao is currently an Instructor of Medicine at the Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine. Dr. Liao received his undergraduate education from Peking University School of Life Sciences; Ph.D. in Biochemistry and Molecular Biology from Peking Union Medical College & Chinese Academy of Medical Sciences, and post-doctoral training at Cleveland Clinic.
Dr. Liao has been named as Distinguished Graduate of Peking University. His Ph.D. thesis work was awarded as “Influential Paper in Cardiovascular Research” by the National Center for Cardiovascular Disease (NCCD), Ministry of Health, China. He is also a proud recipient of the “Jay D. Coffman Young Investigator” Award from Society for Vascular Medicine (SVM), USA.
Dr. Liao’s expertise includes genetic and molecular mechanisms of innate immunity, heart failure and metabolic regulation. His current efforts are focused on (a) transcriptional regulation of cardiac metabolism and mitochondrial biology; (b) roles of myeloid cells in cardiovascular health and diseases. Dr. Liao is currently supported by American Heart Association National Scientist Development Grant.
Transcriptional Control of Mitochondrial Homeostasis by KLF4
The heart has an unrelenting need for energy that is principally generated via mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial dysfunction can contribute to energy starvation and diminution in cardiac function as seen in conditions such as heart failure. Mitochondrial homeostasis is maintained through biogenesis, dynamics, mitophagy clearance as well as regulation of oxidative metabolism. Here we present data demonstrating that KLF4 governs all above aspects of mitochondrial homeostasis in the myocardium through transcriptional regulation.
Two conditional cardiac-specific KLF4 deficient mice lines were generated via the Cre/loxp approach, namely postnatal/adult deletion line (A-cKO) by MHC-Cre and prenatal/embryonic deletion line (E-cKO) by Sm22-Cre. A-cKO and MHC-Cre mice were subjected to transverse aortic constriction (TAC) for studies on mitochondrial function and adaptation to pressure overload in adult myocardium. E-cKO and Sm22-Cre mice were studied from birth to 4-week of age focusing on perinatal mitochondrial biogenesis and dynamics. Primary neonatal rat ventricular myocytes (NRVM) were cultured according to standard protocol and used as an in vitro model for molecular and cell biology studies. Heart function was monitored by echocardiography. Myocardial energetic status, gene expression and regulation, mitochondrial function, dynamics and autophagy/mitophagy flux were assessed.
Within 3 days of TAC, A-cKO mice developed severe heart failure, ATP depletion, and reduction in a broad spectrum of gene targets involved in lipid metabolism and mitochondrial function. Consistent with these observations, isolated mitochondria reveal a significant reduction in oxidative respiration as well as complex I function. Tissue analyses revealed marked alterations in mitochondrial size, structure, and as well as enhanced ROS suggesting impairment in mitochondrial fission, fusion, and/or mitophagy. E-cKO mice exhibited reduced cardiac mitochondrial density, altered mitochondria-myofilament alignment and morphology, suggesting impaired postnatal mitochondrial biogenesis and maturation. Mechanistically, we show that KLF4 binds to and cooperates with ERRα-PGC1α to regulate critical metabolic and mitochondrial targets. Furthermore, KLF4 also transcriptionaly regulates an array of autophagy genes and KLF4 deficiency impaired autophay/mitophjagy flux following mitochondrial damage.
Collectively, our study identifies KLF4 as a critical regulator of mitochondrial function, dynamics and mitophagy. Thus KLF4 governs the transcriptional control of the mitochondrial homeostasis in the myocardium, providing a novel pathway to understand cardiac metabolism and mitochondrial biology as well as potential targets for new therapeutics.
This study is supported by NIH grants to MJ and AHA SDG grant (12SDG12070077) to XL.
Tianxin Yang, Ph.D.
Sun Yet-sen University, China
Tianxin Yang, Ph.D., is Professor of Medicine at University of Uath. He received his Ph.D. degree in Physiology from Tokyo Medicinal and Dental University in 1998. He completed his postdoctoral training at University of Michigan. From 1998-2002, he worked as Staff Fellow and Staff Scientist at National Institute of Health. In 2002, he moved to University of Utah where he went through the rank to Professor with tenure.
Professor Yang’s research program is focused on the role of prostaglandins and PPARgamma in renal physiology and pathophysiology. His research contributes to defining COX-2/mPGES-1/PGE2 pathway and PPARgamma in renal control of fluid metabolism and blood pressure also in renal injury. The breakthrough contributions include the following: 1) elucidation of the distinct regulation of renal cortical and medullary COX-2 expression by dietary salt intake; 2) elucidation of physiological role of mPGES-1 in regulation of renal handling of sodium and blood pressure, 3) the use of conditional knockout technology to define the sodium-retaining action of PPARgamma in the collecting duct, which has unraveled the molecular mechanism of fluid retention side effect of PPARgamma agonists, thiazolidinediones, and 4) the development of nitrated free fatty acids, a new class of endogenous PPARgamma agonists, as a novel therapy for major metabolic and inflammatory diseases. In recognition of his accomplishments, he received numerous prestigious awards including Harry Goldblatt New Investigator from High Blood Pressure Council, Established Investigator Award from American Heart Association, Margret Amundsen Endowed Professorship from University of Utah, and Research Career Scientist Award from the Department of Veterans Affairs. He serves as Ad Hoc and permanent members at grant review committees for American Heart Association and National Institutes of Health. He published over 100 articles, with 60 as first or senior author. These articles appear in Cell Metabolism, PNAS, Circulation Research, J Clin Invest, Hypertension with an accumulative impact factor of 350, and citation times of over 3500. He has delivered over 50 invited lectures at scientific meetings and academic institutions, over 100 regular oral or poster presentations, and he also holds 3 patents.
New mechanism of AngiotensinII-Induced Hypertension: Role of (pro)renin receptor
(Pro)renin receptor (PRR), a newly discovered component of the renin-angiotensin system (RAS), is viewed as a potential regulator of tissues RAS in light of its capability of binding renin and prorenin to increase their catalytic activity. Within the kidney, PRR expression is predominantly expressed in the intercalated cells of the CD where its expression is induced by AngII. The goal of our study was to investigate the mechanism of how AngII activated PRR in the CD cells and further explore the functional implication of this phenomenon. Our focus was placed on defining the COX-2/PGE2/EP4 pathway in regulation of PRR in the CD cells by AngII. In vitro studies demonstrated that AngII stimulated PRR protein expression in primary rat IMCD cells, which was completely abolished by COX-2 inhibitor or EP4 antagonism and to less extent by EP1 but not EP3 antagonism. The medium renin activity varied in parallel with PRR expression level. In vivo studies showed that chronic AngII infusion elevated rat renal medullary PRR expression and the active and total renin levels, all of which were abolished by COX-2 inhibition or EP4 antagonism, accompanied by a significant attention of hypertension development. Delivery of a PRR inhibitor to the renal medulla of SD rats attenuated AngII-induced hypertension, kidney injury, and renal medullary α-ENaC expression. Overall, renal medullary PRR expression is under the control of COX-2/PGE2/EP4 pathway and mediates AngII-induced hypertension.
Yu Huang, Ph.D.
Chinese University of Hong Kong, China
Professor HUANG Yu received his B.Sc. degree from Fudan University Shanghai Medical School and Ph.D. degree from University of Cambridge. He is currently the Professor of Biomedical Sciences in School of Biomedical Sciences. He is the founding Director (Basic Sciences) of Institute of Vascular Medicine at Chinese University of Hong Kong and he is currently the President of Asian Society for Vascular Biology. Professor Huang’s team has been actively exploring clinically-relevant research aiming to elucidate cellular and molecular events involved in the initiation and progression of endothelial cell dysfunction in hypertension, obesity, diabetes, estrogen deficiency and ageing, to uncover novel relevant biomarkers for vascular pathogenesis, and to develop venues to reverse vascular dysfunction in animal models of cardio-metabolic disorder, as well as to train top-quality research students. He has co-authored 328 peer-reviewed publications in SCI-indexed journals. He has so far served as the editor, associate editor, and editorial board member for 35 journals.
PPARs agonists and vasoprotection
The PPARs agonists are found to raise insulin sensitivity in diabetes. It however remains to be further elucidated concerning the role of PPARg or PPARδ and sites of their actions across the vascular wall in regulating NO bioavailability and thus vascular function. We have recently investigated the target cells for PPAR agonists to restore endothelial function in diabetic and obese mice. We reveal that adipocyte-derived adiponectin plays an obligatory role in mediating the beneficial effect of PPARγ on vascular endothelium of diabetic mice through activating AMPK/eNOS and cAMP/PKA pathways to increase NO bioavailability and reduce oxidative stress. PPARγ activation by rosiglitazone restores endothelium-dependent relaxations, whereas diabetic mice lacking adiponectin or treated with an anti-adiponectin antibody do not respond. PPARγ agonist triggers adiponectin release from fat explants, and subcutaneous fat transplantation from rosiglitazone-treated mice rescues endothelial function in untreated db/db recipients. Thus, the adipose tissue represents a promising target for treating diabetic vascular complications. On the other hand, PPARδ agonist improves endothelium-dependent relaxation and flow-mediated vasodilatation most likely through a direct effect on endothelial cells to increase NO bioavailability via PI3K/Akt/eNOS signaling. We have also recently shown that metformin improves endothelial function in diabetic and obese mice through activation of PPARδ. These results support the therapeutic value of PPAR agonists or activators for diabetic vasculopathy but targeting different cell types. (Supported by Hong Kong CRF and GRF)
Steven R. Houser, Ph.D., FAHA
Temple University School of Medicine, USA
Steven Houser, Ph.D., FAHA is the Laura H. Carnell Professor of Physiology and Medicine, Director, Cardiovascular Research Center and Chair of Physiology at Temple University School of Medicine. His laboratory has been actively involved in cardiovascular research for over 30 years. His science has focused on the fundamental biology of cardiac myocytes and their response to pathological stress. His research initially focused on the electrical and mechanical properties of the heart and the alterations in these properties that contribute to depressed cardiac performance in heart failure. Dr. Houser was one of the first investigators to develop techniques for isolation of Ca2+ tolerant myocytes from large animals. Using these cells, the Houser laboratory defined fundamental aspects of excitation-contraction coupling and Ca2+ regulation in the normal heart. The Houser laboratory was also one of the people to define the alterations in myocyte Ca2+ regulation that underlie poor contractility and arrhythmias in heart failure. His work has focused on the alterations in myocyte Ca2+ regulation that cause depressed contractile reserve in the failing human heart and predispose the heart to arrhythmias.
Dr. Houser’s recent research has focused on the idea that heart failure does not result from fundamental defects in myocyte Ca2+ regulation, but instead, from Ca2+ mediated cell death. Current studies are exploring the idea that the increased Ca2+ necessary for the myocytes of the dilated, failing heart to work against increased systolic wall new stress, induces alterations in myocyte Ca2+ handling (in an attempt to prevent cellular Ca2+ overload) and predisposes the myocyte to apoptosis and necrosis. This new research challenges the dogma that increasing cardiac myocyte Ca2+ (and contractility) is a desirable therapeutic strategy. Novel strategies to reduce the excess Ca2+ involved in cell death signaling are being studied.
The Houser laboratory is also exploring the idea that heart failure results from a loss of functional cardiac myocytes, and that increasing myocyte number, with cell therapy, can restore more normal function to the failing heart. Approaches that enhance phasic Ca2+ entry into cardiac precursor cells are being tested for their cardiogenic potential. The ultimate goal of the work in the Houser laboratory is to develop therapeutic strategies to better treat patients suffering with poor cardiac pump function.
Dr. Houser is an internationally renowned researcher, who has led the way for many important discoveries about the heart disease. His work has been supported consistently by the National Institutes of Health since 1984. Including a grant in 2005 to determine the presence of cardiac stem cells and whether they can be used to fight heart failure. In 2002 he won the University Faculty Award for Research in recognition of his pioneering work. In 2003 he founded the Cardiovascular Research Center. His research focuses on processes that maintain the electrical and contractile properties of normal heart functions and the defects in these processes that lead to issues such as arrhythmias and congestive heart failure.
TRPC Channels Contribute to Pathological Hypertrophy and
Depressed Contractility after Myocardial Infarction
Transient receptor potential (TRPC) channels are not expressed in abundance in the normal adult heart but their expression increases in pathological stress. We tested the idea Calcium influx through TRPC channels contributes to pathological hypertrophy and depressed myocyte contractility. Myocardial infarction (MI) was induced in mice. Over time there was an increase in TRPC channel expression and this was associated with pathological structural and functional remodeling. TRPC channels were found to induce activation of pathological hypertrophy signaling and to induce calcium loss (leak) from the
sarcoplasmic reticulum. This calcium leak reduced the inotropic effectiveness of catecholamines. Expressing a dominant negative TRPC that induced loss of channel function blunted pathological remodeling after MI. These results suggest that TRPC channels are a viable therapeutic target for patients who have suffered an MI.
Walter J. Koch, Ph.D., FAHA
Temple University School of Medicine, USA
Professor Walter J. Koch (Ph.D., Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 1990) started his career at Duke University Medical Center and Howard Hughes Medical Institute as a postdoctoral fellow (1990-1995) in the lab of Dr. Robert Lefkowitz (Nobel Prize in Chemistry, 2012) and advanced to tenured Professor of Surgery before moving to Thomas Jefferson University in 2003 to build a Center for Translational Medicine. He became the Chairman of Dept. Pharmacology and Director of Center for Translational Medicine at Temple University in 2012. As principal investigator and project leader of several multimillion dollar NIH grants, Koch has overseen numerous advances in cardiac research over the last two decades. His research work has revealed the novel roles G protein-coupled receptor kinases (GRKs) play in cardiac injury and repair. Manipulating these GRKs, and targeting them with therapeutics, could lead to new treatments for heart failure patients. In fact, inhibition of one GRK, GRK2, in the heart has led to the reversal of heart failure in several animal models. This has been shown to occur by using a gene therapy approach in pre-clinical studies in both small and larger animal models and this methodology is one step away from human clinical trials. Further, small molecule inhibitors of GRK2 are now emerging. He has trained over 40 research Fellows and several have gone on to lead their own labs. Numerous awards and honors have recognized Koch’s research, including the International Society for Heart Research 2011 Outstanding Investigator Award, the American Heart Association Thomas Smith Memorial Lecture and Award for Cardiovascular Signaling in 2009, and a National Institutes of Health 10-year MERIT award running through 2019. He has published >350 peer-reviewed articles. He has served on NIH study sections as both a reviewer and Chair. He is the outgoing Chair of the Basic Cardiovascular Sciences Council of the American Heart Association and a current Associate Editor of Circulation Research.
GRK2 Inhibition for Heart Failure Treatment: Nearing Translation
We have spent the last two decades investigating novel molecular targets for correcting ventricular dysfunction in heart failure. We have identified the G protein-coupled receptor (GPCR) kinase-2 (GRK2) as such a target. We have shown that inhibiting the activity of this kinase or genetic deleting this kinase in the heart can prevent and reverse heart failure in mouse models. Moreover, a gene therapy approach with a peptide inhibitor of GRK2 (ARKct) has been used in several small and large animal models to rescue heart failure. This includes a recent study in a pre-clinical pig model of heart failure and ARKct gene delivery reversed ventricular dysfunction and caused reverse remodeling. A clinical trial is being planned and these studies will be presented. In addition to a gene therapy approach for GRK2 inhibition we are pursuing small molecule pharmacological inhibition and recent studies have shown the FDA approved anti-depressant drug paroxetine is a specific GRK2 target outside its actions to prevent serotonin re-uptake. We have unpublished results that will be presented at this meeting that paroxetine can reverse heart failure in an animal model and this therapeutic effect is independent to its CNS effects. This paves the way for paroxetine derivatives and other small molecules to target GRK2 for future heart failure therapy.
Jeffery D. Molkentin, Ph.D.
Cincinnati Children’s Hospital Medical Center, USA
Dr. Molkentin received his Ph.D. from the Medical College of Wisconsin (USA) in 1994, after which he performed postdoctoral training with Dr. Eric Olson in Texas (USA) from 1994-1997, followed by his first faculty appointment in 1997 at the Cincinnati Children’s Hospital Medical Center of the University of Cincinnati (USA), where today he is a Full Professor. Dr. Molkentin has published over 315 original articles during this time and is funded with multiple NIH grant awards. Dr. Molkentin was a Pew Scholar early in his career and is now a full investigator of the Howard Hughes Medical Institute in the USA. Dr. Molkentin’s research program continues to focus on the identification of candidate genes and signaling pathways involved in cardiac hypertrophy, contractility, cell death, heart failure, and muscular dystrophy, as well as mitochondria- dependent necrosis. Dr. Molkentin has placed most of his 60+ trainees in academics or the pharmaceutical industry.
c-kit+ Cells Minimally Contribute Cardiomyocytes to the Heart During Development, Aging or After Injury
In the last decade a number of different cell sources have been implicated in contributing to the myocardium after injury to regenerate this organ. One of the most highly studied has been c-kit+ cardiac progenitor cells (CPCs) that reside in the heart where they subsequently contribute differentiated lineages to help regenerate the heart However, the extent to which this process occurs in vivo has been a source of great debate. Here we generated two mouse models in which a cDNA cassette expressing either the tamoxifen inducible MerCreMer protein or a standard Cre protein were “knocked” into the endogenous Kit locus (c-kit encoding gene). The mice were cross-bred to reporter mice containing a conditional eGFP expression locus that upon Cre recombinase activation in any tissue, marked cells irrevocably. We performed long-term lineage tracing in the heart as well as after myocardial infarction. Analysis of bone marrow and testis demonstrated abundant labeling with the Kit-MerCreMer and Kit-Cre approach, demonstrating the fidelity and robustness of the approach and the knockin alleles. The results show that endogenous c-kit+ cells can indeed contribute to the myocyte fraction of the heart, although at a rate of 0.03% or less. Moreover, the majority of c-kit+ lineage-identified myocytes within the adult heart after myocardial infarction injury are the result of cell fusion, not bonafide new myocyte formation. However, c-kit+ lineage derived cells substantially contribute to other cell types within the adult heart, most notably endothelial and CD34+ cells. Thus, endogenous c-kit expressing cells do contribute differentiated cell types to the heart, although their ability to generate cardiomyocytes is extremely limited.
Ruth S. Slack, Ph.D.
University of Ottawa, Canada
Dr. Slack is a full professor at the University of Ottawa in the Department of Cellular and Molecular Medicine. The long term goals of Dr. Ruth Slack and her research group are to activate endogenous stem cells to promote the regeneration of the damaged brain after stroke or in neurodegenerative diseases. Dr. Slack’s group has also shown that manipulation of mitochondrial dynamics has a major impact on neuronal survival after injury. Their most recent studies have shown that mitochondria can be reconfigured, where they change their shape to enhance their efficiency of ATP production and reduce the generation of ROS, even under hypoxic conditions. Manipulation of mitochondrial dynamics can enable mitochondria to generate ATP and become more resistant to stress. Presently the lab is focusing on novel strategies to enhance mitochondrial function under stress conditions.
Mitochondrial restructuring to enhance efficiency of
ATP production and resistance to stress
Sustained cellular function and viability of high-energy demanding post-mitotic cells rely on the continuous supply of ATP. The utilization of mitochondrial oxidative phosphorylation for efficient ATP generation is a function of oxygen levels. As such, oxygen deprivation, in physiological or pathological settings, has profound effects on cell metabolism and survival. Here we show that it is possible to reprogram mitochondrial to preserve efficient ATP production regardless of oxygen levels. Mild extracellular acidosis triggers a rapid and reversible homeostatic program that restructures mitochondria, by regulating mitochondrial dynamics and cristae architecture, to reconfigure mitochondrial efficiency, maintain mitochondrial function and cell survival. Preventing mitochondrial remodeling results in mitochondrial dysfunction, fragmentation and cell death. Our findings demonstrate that mitochondrial morphology can dictate the bioenergetic status of post-mitotic cells. Current studies are in progress to identify the key molecular targets to induce mitochondrial reprogramming.
King’s College London, UK
Professor Xu qualified in Medicine in China and undertook postgraduate research training at Peking Union Medical College and then the University of Innsbruck Medical School in Austria. He was appointed Professor in Cardiovascular Science at St George’s Hospital in 2000 and then to the BHF John Parker Chair of Cardiovascular Sciences at King’s College London in 2006. He has a very prominent international profile in vascular biology as evidenced by numerous invited lectures at national and international scientific meetings, chairing of many research conferences, service on the editorial boards of eminent journals (e.g. Consulting Editor, ATVB), and membership of national and international committees. He edited the widely used guide ‘Handbook of Mouse Models of Cardiovascular Disease’. Professor Xu has been honored with the Austrian Cardinal Prize for Medicine in 1993, the Rokitansky Prize for Pathology in 1995, and several visiting professorships. Professor Xu has made the important finding on the presence of stem/progenitor cells in the adventitia of the vessel wall. Professor Xu has also introduced several innovative experimental techniques to research in the above areas. One was establishing the first mouse model of vein bypass graft atherosclerosis in 1998, which is now widely used internationally. Professor Xu’s original work has contributed to the research field as indicated by his publication list that includes many highly cited papers (H-index 67; June 2014). He has an excellent record of training research scientists, several of whom have progressed to distinguished independent careers throughout the world – eg, 5 Professors and department chairs and 10 Assistant/Associate Professors (lecturers/Senior Lecturers) in UK, USA, Germany, Austria and China.
Vascular Stem Cells in Arteriosclerosis and Tissue-engineered Grafts
Accumulating evidence confirmed the presence of resident stem/progenitor cells in the adventitia and intima of the vessel wall. Vascular lineage differentiation of stem cells can contribute to both tissue repair and exacerbation of vascular diseases. The present presentation will focus on two aspects of progenitor cell plasticity in vascular disease. Firstly, we provide evidence that macrophages can induce functional endothelial cell differentiation of the stem cells while simultaneously inhibiting their smooth muscle cell differentiation. Mechanistically, both effects were mediated by macrophage-derived TNF-α via TNF-α receptor 1 (TNF-R1) and canonical NF-κB activation. The lack of TNF-α in a knockout mouse model of vein graft resulted in significant reduction of endothelial repair that led to thrombus formation. Furthermore, we found that treatment of the cells with sirolimus resulted in an induction of their migration and is mediated specifically by CXCR4 activation. Ex vivo experiments using a decellularised vessel in a bioreactor system confirmed the increment of vascular progenitor migration from the adventitial side into the intima where they form neointima-like lesions in response to sirolimus. Thus, vascular progenitor cells can differentiate into either endothelial cells to repair the vessel or smooth muscle cells to form neointimal lesions. A balance of stem/progenitor cell differentiation would be essential for vascular hemostasis.
Stem cells have been proven to be potential source of vascular cells for tissue-engineered grafts. Recently, we designed a combined protocol of reprogramming and differentiation of human fibroblasts. Four reprogramming factors (OCT4, SOX2, KLF4, c-MYC) were overexpressed in fibroblasts under reprogramming conditions for 4 days with cells defined as partially induced pluripotent stem (PiPS) cells. PiPS cells did not form tumours in vivo after subcutaneous transplantation in SCID mice and differentiated into endothelial and smooth muscle cells when seeded on collagen IV and maintained in differentiation media. PiPS-SMCs repopulated decellularized vessel grafts and ultimately gave rise to functional tissue-engineered vessels when combined with previously established PiPS-endothelial cells, leading to increased survival of SCID mice after transplantation of the vessel as a vascular graft. Additional, we have also used c-Kit-cells isolated form stem cells that can differentiate into functional endothelial and smooth muscle cells. When seeded ex-vivo on a decellularized vessel, c-Kit+ cell-derived endothelial cells organized in a uniform monolayer, expressing endothelial markers. In vivo, implantation of the tissue-engineered vessel in a mouse model led to a markedly reduced neointima formation and mortality, as compared to the non-seeded controls. Thus, we developed a protocol to generate endothelial and smooth muscle cells from stem cells or PiPS cells, useful for generating tissue-engineered vessels.
Pingjin Gao, Ph.D.
Shanghai Jiao Tong University, China
Dr. Gao is the Vice Director of Shanghai Institute of Hypertension, and Director of Shanghai Key Laboratory of Hypertension. She is also the principle investigator for Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine.
1) Diagnosis and therapy of intractable hypertension, including screening for secondary hypertension;
2) The establishment and application of genetic hypertension resources (Dr Gao’s team has collected many samples, including hypertensive patients, normotensive subjects, nuclear families and sib-pairs);
3) The mechanisms of vascular remodeling in hypertension, her main focus being the evaluation of vascular structure and function induced by inflammation in vascular injury;
4) Screening and identifying new biomarkers in vascular injury for developing therapeutic strategies related to hypertension..
Complement-mediated macrophage polarization in perivascular adipose tissue contributes to deoxycorticosterone acetate-salt-induced vascular injury
Objective: We have previously shown an increased expression of complement 3 (C3) in perivascular adipose tissue (PVAT) in the deoxycorticosterone acetate (DOCA)-salt hypertensive model. This study aims to determine the role and underlying mechanism of C3 in PVAT and the pathogenesis of hypertensive vascular remodeling.
Approach and Results: We found that C3 is primarily expressed in macrophages in PVAT of blood vessels from DOCA-salt mice. We then investigated the role of C3 in macrophage polarization using peritoneal macrophages from wild-type (WT) and C3-deficient (C3KO) mice. We found that C3KO macrophages have decreased M1 but increased M2 phenotypic markers expression. In vivo bone marrow transplantation (BMT) studies further showed that DOCA-salt recipient mice have fewer M1 and more M2 macrophages in PVAT when the donor bone marrow was from C3KO compared to WT mice, accompanied with an ameliorated vascular hypertrophy and fibrosis. Furthermore, we found that complement 5a (C5a) is important in macrophage polarization as well as DOCA-salt induced vascular hypertrophy and fibrosis. Consistently, depletion of macrophage in vivo prevented the induction of C3 and C5a in PVAT, and ameliorated pathological vascular remodeling.
Conclusions: The presence and activation of bone marrow-derived macrophages in PVAT is crucial for complement activation in hypertensive vascular inflammation, and C5a plays a critical role in DOCA-salt induced vascular injury by stimulating macrophage phenotypic modulation towards to a more M1 and less M2 state in PVAT.
Nanping Wang, Ph.D.
Peking University, China
Dr. Wang received his medical degree at Xi’an Medical University in 1986 and his Ph.D. at Beijing Medical University in 1994. He obtained postdoctoral training in Europe and the United States. He had been an assistant professor of research in University of California Riverside and San Diego. Since 2003, he has been a full professor at Peking University Health Science Center and associate director in the Institute of Cardiovascular Science and the Diabetes Center. The research in his lab has been focused on the molecular mechanisms and novel therapeutic targets of major metabolic vascular diseases with emphases on atherosclerosis, in particular, the roles of nuclear hormone receptors and mechanobiology. Dr. Wang has been the leading scientist of the National Major Research Program “Nuclear Receptors Regulation of Glucose and Lipid Metabolism” and a recipient of several major national research grants. He has published over 70 articles in peer-reviewed journals such as Circulation, Proc Natl Acad Sci USA, Circ Res, Hypertension and ATVB.
Dr. Wang has served as the Secretary-in-General for the Asian Society of Vascular Biology, a member of the Advisory Board of the National Science Foundation of China, Department of Medical Sciences, a Vice Chairman of the Steering Committee for the National Research Program for “Vascular Homeostasis and Remodeling”.
Xenobiotic Receptor PXR Regulates Innate Immunity via Activation of NLRP3 Inflammasome in Vascular Endothelial Cells
Pregnane X receptor (PXR) is a member of nuclear receptor superfamily and responsible for the detoxification of xenobiotics. Our previously study demonstrated that PXR is expressed in endothelial cells (ECs) and acts as a master regulator of detoxification genes to protect ECs against xenobiotics. Vascular endothelial cells are key sentinel cells to sense the pathogens and xenobiotics. In this study, we examined the potential function of PXR in the regulation of innate immunity in vasculatures. Treatments with PXR agonists or overexpression of a constitutively active PXR in cultured ECs increased gene expression of the key pattern recognition receptors (PRRs), including toll-like receptors (TLR-2, -4, -9), and NOD-like receptors (NOD-1,-2 and NLRP3). In particular, PXR agonism triggered the activation of NLRP3 inflammasome and the ensuing cleavage and maturation of caspase-1 and interleukin-1β (IL-1β). Conversely, selective antagonism or gene silencing of PXR abrogated NLRP3 inflammasome activation. In addition, we identified NLRP3 as a transcriptional target of PXR by using the promoter-reporter and chromatin immunoprecipitation (ChIP) assays. In summary, our findings revealed a novel regulatory mechanism of innate immune by PXR, which may act as a master transcription factor controlling the convergence between the detoxification of xenobiotics and the innate immunity against them.
Bao-Liang Song, Ph. D.
Wuhan University, China
Dr. Bao-Liang Song is a Professor of Biochemistry, Dean of College of Life Sciences, Wuhan University, Wuhan China. He received a B.A. degree from Nanjing University, China in 1997. He obtained his Ph.D. degree at Shanghai Institute of Biochemistry and Cell Biology in 2002. From 2002 to 2005, Dr. Song received his post-doctoral training in the laboratory of Drs. Joseph L. Goldstein and Michael S. Brown at UT Southwestern Medical Center. He has been an independent PI in Shanghai Institute of Biochemistry and Cell Biology since 2005. He has been appointed as a Professor and Dean of College of Life Sciences, Wuhan University since 2014.
Dr. Song focuses on cholesterol homeostasis. He has made significant contributions to the field as follows. 1) His lab has uncovered the mechanism of intestinal cholesterol absorption. They demonstrate that Niemann Pick C1 Like 1 (NPC1L1) mediates cholesterol uptake via vesicular endocytosis. They have identified most of the factors in this pathway including: Numb, Flotillins, Cdc42 and MyoVb/Rab11a/Rab11FIP2. The regulatory mechanism and functions of these proteins are also studied. 2) Dr. Song has delineated the pathway the cholesterol-regulated degradation of HMG-CoA reductase, which is one of the major mechanisms governing cholesterol synthesis. He has identified the E3 gp78, endogenous regulator lanosterol and other cofactors such as Ufd1. These findings have been published in Nat Med, Cell Metab, Mol Cell, PNAS and JBC. Besides cholesterol absorption and biosynthesis, his lab is also studying intracellular cholesterol trafficking and cholesterol-related diseases.
Dr. Song’s lab is one of the leading players of this field. Dr. Song was appointed as Chief Scientist by the Ministry of Science and Technology of China, and won China National Funds for Distinguished Young Scientists. He was awarded with Tan Kah Kee Young Scientist Award in Life Sciences and Arthur Kornberg Memorial Award. He is a steering committee of International Conference on the Bioscience of Lipids (ICBL). He has served as Editorial Board Member of JBC and Associated Editor of J of Mol. Biol. Chem.
Mechanism of Intestinal Cholesterol Absorption
and Intracellular Cholesterol Transport
Niemann Pick C1 Like 1 (NPC1L1) is a polytopic transmembrane protein responsible for intestinal cholesterol absorption. We have shown that NPC1L1 mediates cholesterol uptake via vesicular endocytosis. The mechanism of sterol-stimulated NPC1L1 internalization is still mysterious. Recently, we identified an endocytic peptide signal, YVNXXF (where X stands for any amino acid), in the cytoplasmic C-terminal tail of NPC1L1. Cholesterol binding on the N-terminal domain of NPC1L1 released the YVNXXF-containing region of NPC1L1 from association with the plasma membrane and enabled Numb binding. We also found that Numb, a clathrin adaptor, specifically recognized this motif and recruited clathrin for internalization. Disrupting the NPC1L1-Numb interaction decreased cholesterol uptake. Ablation of Numb in mouse intestine significantly reduced dietary cholesterol absorption and plasma cholesterol level. Together, these data show that Numb is a pivotal protein for intestinal cholesterol absorption and may provide a therapeutic target for hypercholesterolemia.
In addition, cholesterol is unevenly distributed in cellular membrane structures and dynamically transported in cells. The ER membrane contains only about 0.5-1% of total cellular cholesterol. Yet the cholesterol concentrations are higher in the Golgi apparatus and highest (about 60-80%) in the plasma membrane (PM). This cholesterol gradient is pivotal for protein secretion, endocytosis and vesicular transport. The mechanism of intracellular cholesterol transport is a fundamental question in cell biology and poorly understood. With the aim to identify critical proteins for intracellular cholesterol transport, we developed an elegant cellular screening system and performed a genome-wide shRNA screen using it. The progresses about intracellular cholesterol transport in this lab will be discussed.
Christoph Schmitt, Ph.D.
Christoph became a member of the Nature Communications team in January 2012 after spending a year at Nature Reviews Cardiology and Nature Reviews Clinical Oncology. He is now a Senior Editor and Locum Team Manager at Nature Communications. Prior to joining Nature Publishing Group, Christoph studied Pharmacy at the University of Heidelberg (Germany) and, in his doctoral thesis at the University of Vienna (Austria), focused on the regulation of endothelial nitric oxide production. During his postdoctoral work at University College London, Christoph investigated mitochondrial function and cell proliferation. Christoph is based in Nature Communication’s London office.
Nature Communications - our editorial criteria and ambitions in China
In this presentation I describe the aims and scope of Nature Communications, and where the journal sits within the Nature family of journals. Furthermore, I explain why we feel Nature Publishing Group, and in particular Nature Communications, can be of high value for Chinese researchers. I will also comment on the editorial criteria that determine whether a manuscript is sent out to peer-review and provide insight into our decision making process when a manuscript has completed peer-review, hoping to provide general advice that will help members of the audience to maximize the potential for success when submitting your manuscript to the Nature family of journals.
Qingping Feng, M.D., Ph.D.
University of Western Ontario, London, Canada
Dr. Qingping Feng obtained his MD from Southeast University Medical School, Nanjing, China (1978-1983), PhD in pharmacology from the University of Gothenburg, Sweden (1989-1993), and postdoctoral training at the University of Western Ontario, Canada (1993-1995). He is currently a Professor of Physiology, Pharmacology, and Medicine at Schulich School of Medicine and Dentistry, the University of Western Ontario, and a senior scientist at Lawson Health Research Institute. Dr. Feng received a Career Investigator Award from the Heart and Stroke Foundation of Ontario, Canada (2005-2015) and Dean’s Award of Excellence from the Faculty of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario in 2009. He is currently Vice President of the Canadian Nitric Oxide Society. His research is focused on embryonic heart development and adult diseases that affect the heart including myocardial infarction, diabetes and sepsis. He has published over 90 peer-reviewed original papers in excellent journals including Circulation, European Heart Journal, Diabetes, Stem Cells, Cardiovascular Research, and Critical Care Medicine. His work has increased our understanding on the role of nitric oxide in heart failure and embryonic heart development, and provided insights for novel therapeutic strategies in the treatment of myocardial infarction and sepsis.
ROS Signaling Regulates Embryonic Heart Development
Women with pregestational diabetes are at a high risk of having babies with congenital heart defects (CHDs). The mechanisms of CHD induction in the offspring of women with pregestational diabetes remain elusive. With an ever-increasing rate of diabetes in young adults, there is a pressing need to understand the underlying mechanisms and initiate effective preventative strategies. Reactive oxygen species (ROS) mediate a number of cellular processes during embryonic development including cell proliferation, differentiation and migration. A notable source of cellular ROS is produced by NADPH oxidase, which has 5 isoforms (NOX 1-5). Despite the well-known physiological roles of ROS, its significance in fetal heart development is not well defined. We aimed to study the role of ROS signaling in heart morphogenesis and unravel molecular mechanisms of CHDs induced by pregestational diabetes. To this end, a mouse model of pregestational diabetes induced by streptozotocin was employed. A spectrum of septal, conotruncal and coronary artery malformation were identified in the offspring of mice with pregestational diabetes. ROS levels were elevated and glutathione levels were diminished in the fetal hearts of diabetic mice. Oral treatment with an antioxidant N-acetylcysteine (NAC) significantly diminished the incidence of CHDs and prevented coronary artery malformation in the offspring of pregestational diabetic mice. Furthermore, pregestational diabetes reduced cell proliferation, altered transcript levels, and disrupted epithelial to mesenchymal transition (EMT) in the fetal heart of diabetic mice, which were all prevented by NAC treatment. To further study the role of basal ROS production in embryonic heart development, a NADPH oxidase Nox2 knockout mouse was utilized. We demonstrated that loss of Nox2 expression decreased ROS production, and impaired TGF-b/BMP signaling and endocardial EMT in embryonic heart. This ultimately resulted in cardiac septum and valve defects. Thus, under normal physiological conditions ROS production promotes heart development whereas excess ROS levels during pregestational diabetes induce CHDs. These studies show maintaining a balance of ROS levels is essential for normal embryonic heart development in mice. Furthermore, NAC may have therapeutic potential in preventing the development of CHDs during pregestational diabetes.
Issei Komuro, Ph.D.
The University of Tokyo Graduate School of Medicine, Japan
Dr. Issei Komuro is currently a Professor and chairman, Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine and a PI of CREST, Japan Science and Technology Agency. Dr. Komuro was graduated from The University of Tokyo in 1982 and after clinical training, he has started research on mechanisms of cardiac hypertrophy in the Department of Medicine III, The University of Tokyo School of Medicine. He elucidated mechanisms of stretch-induced cardiomyocyte hypertrophy by developing in vitro stretch device. After obtaining Ph.D. from The University of Tokyo, he became a postdoctoral fellow in Molecular Medicine Unit and Cardiovascular Division, Beth Israel Hospital/Harvard Medical School in 1989. He studied cardiac development and isolated cardiac specific homeobox gene Nkx2.5. After returning to The University of Tokyo, he has reported that angiotensin II type 1 receptor is involved in mechanical stress-induced cardiac hypertrophy independent of angiotensin II and has recently reported novel mechanisms of heart failure such as ischemia, inflammation and aging. Dr. Komuro was promoted to be Professor in Medicine, Chairman, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine in 2001 and Professor and chairman, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine in 2009. From 2012, he is a professor of The University of Tokyo Graduate School of Medicine. He has published more than 700 papers on peer-review journals including Nature, Cell, Nature Medicine, Lancet and Circulation. He was awarded ACC/Merck fellowship award in 1991, Outstanding Investigator Prize from ISHR in 2003 and President’s Distinguished Lecture Award from ISHR in 2010. He has been a visiting professor of Zhongshan Hospital, Fudan University in Shanghai since 2009 and he received an honorary Professorship from Harbin Medical School, Harbin in 2014. He currently serves in the editorial board of Journal of Clinical Investigation, Circulation Research, Journal of Molecular and Cellular Cardiology, Arteriosclerosis, Thrombosis, and Vascular Biology, Cardiovascular Research and Circulation Journal.
Molecular mechanisms of heart failure - angiogenesis and aging
Department of Cardiovascular Medicine, the University of Tokyo Graduate School of Medicine, Japan Prolonged cardiac hypertrophy causes heart failure, but its mechanisms are largely unknown. Recently we have reported three mechanisms of heart failure. Pressure overload, which is produced by constricting transverse aorta of mice, induced cardiac hypertrophy without cardiac dysfunction until 14 days and initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors. After 14 days, however, sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. We have recently found that three miRNAs, which are targets of p53, are upregulated in blood of patients showing heart failure within 1 year after myocardial infarction.
Complement C1q is increased with aging and activates canonical Wnt signaling. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Recently we found that the C1q-wnt signaling pathway also plays a critical role in the development of heart failure and arteriosclerosis.
Yibin Wang, Ph.D.
University of California Los Angeles, USA
Dr. Yibin Wang is currently a Professor of Molecular Medicine in the Departments of Anesthesiology, Physiology and Medicine, David Geffen School of Medicine at UCLA. He is the Vice Chair for Research and Director of the Division of Molecular Medicine in the Department of Anesthesiology. He is also a member of the Molecular Biology Institute and California NanoScience Institute at UCLA. Dr. Wang received his Ph.D. in molecular genetics and cell biology from Baylor College of Medicine and post-doctoral training at The Scripps Research Institute and University of California at San Diego. Dr. Wang’s expertise includes genetic and molecular mechanisms of heart failure and metabolic regulation with particular interest in development of novel models and gene discovery as novel therapeutic targets for human cardiovascular and metabolic diseases. Dr. Wang received an Established Investigator Award from American Heart Association from 2005 to 2010. He was awarded in 2009 Changjiang Scholar from Minister of Education, China and elected as National Expert for “Thousand Talent Plan” in 2011 and currently holds a visiting professor position at Center of Translational Medicine at SJTU, Shanghai, China. In 2013, he received an honorary Professorship from Peking Union Medical College, Beijing, China. He currently serves in the editorial board of Journal of Biological Chemistry, Circulation Research, Journal of Molecular and Cellular Cardiology and Journal of Cardiac Failure, Dr. Wang has published over 140 peer-reviewed manuscripts in many top ranked scientific journals, including Nature Medicine, Journal of Clinical Investigation, Circulation and Circulation Research, and holds two current patents that are licensed by biotech/Pharma. Dr. Wang is currently serving as principal investigator for several NIH grants and supervising mentor for trainee fellowships from NIH and AHA. He is a member of the leadership committees for AHA, ISHR North American Section and America Physiological Society. His past publication can be found at http://www.anes.ucla.edu/~yibinwang/publications.html.
In his lecture, Dr. Wang will present the recent findings on the genetic basis of cardiac hypertrophy and fibrosis based on systems genetic analysis.
Systems Genetics for Heart Failure - Go Beyond the Genome
The pathogenesis of heart failure is complex, involving heterogeneous genetic and environmental factors. The common genetic variants that account for the vast majority of disease are largely unknown. Genome-wide association studies (GWAS) have had limited success for human heart failure, in part because the disease is age and sex dependent, and the disease progression is affected different etiology, life style and other environmental factors. Consequently, the genetic factors contributing to heart failure remain poorly understood and remain to be a major challenge to fully understand the heterogeneity of the disease and to develop more effective and personalized therapies.
Recognizing these limitations, we have developed a novel approach by combining comprehensive phenotype and molecular studies with GWAS across a hybrid mouse diversity panel (HMDP) under a well defined pathological stressor to systematically map genetic factors and molecular networks implicated in heart failure. The HMDP consists of > 100 common inbred and recombinant inbred (RI) strains which have been either entirely sequenced or densely genotyped [over 140,000 single nucleotide polymorphisms (SNPs)]. By comprehensive phenotypic analysis, we have found striking differences in the response to isoproterneol stimulation among HMDP strains and identified numerous novel genes and gene networks associated with specific cardiac pathological features, including hypertrophy, dysfunction, gene expression, sudden death and fibrotic remodeling. These exciting new findings demonstrate a significant genetic contribution to specific features of cardiac remodeling, and the systems genetic approach have revealed novel mechanisms and potential molecular targets for diagnosis and therapy for heart failure.
Liangyou Rui, Ph.D.
The University of Michigan Medical School, USA
Dr. Rui is currently Professor of Molecular and Integrative Physiology, Professor of Internal Medicine, the University of Michigan Medical School. Dr. Rui obtained his Ph.D. from the University of Michigan Medical School, and completed his postdoctoral training at the Joslin Diabetes Center, Harvard Medical School. Dr. Rui’s research is centered on obesity, type 2 diabetes, and fatty liver diseases. Dr. Rui first cloned the SH2B1β isoform, and his team first discovered SH2B1 as a murine obesity gene. Mechanically, brain SH2B1 promotes weight loss in part by enhancing central leptin and insulin action. Dr. Farooqi, in collaboration with Dr. Rui, recently demonstrated that SH2B1 missense mutations are associated with human obesity. Dr. Rui’s team recently identified a novel molecular connection coupling inflammation to metabolic disease. His group first reported that liver inflammation increases hepatic glucose production by promoting the hyperglycemic response to glucagon, a key counterregulatory hormone. NF-κB-inducing kinase (NIK) and TRAF family members molecularly link proinflammatory cytokines and cellular stress to counterregulatory hormone hypersensitivity. These pioneer studies raise the possibility that metabolic inflammation is likely to disrupt insulin/counterregulatory hormone balance in obesity, leading to type 2 diabetes and diabetes-associated complications. Dr. Rui’s research programs are well funded by the NIH grants and the American Diabetes Association (ADA) research awards. Dr. Rui was a recipient of the prestigious ADA career development award. Dr. Rui serves as a grant reviewer in the NIH study sections (CADO and IPOD), Veterans Administration study sections (Endo-A), ADA study sections, and National Natural Science Foundation of China (NNSFC). He also serves as an editorial board member for Journal of Biological Chemistry, Endocrinology, and American Journal of Physiology-Endocrinology and Metabolism.
Identification of obesity gene SH2B1 and the mechanism of its action
Obesity is the primary risk factor for metabolic disease and cardiovascular disease. Both genetic and environmental factors contribute to obesity development, and genetic predisposition exacerbates obesity progression in the current obesogenic environment. However, only a handful of “obesity” genes have been identified in humans. We have systemically analyzed the metabolic function of SH2B1 and characterized SH2B1 as an obesity gene in both rodents and humans. SH2B1 is an SH2 and PH domain-containing signaling molecule and promotes cell signaling in response to leptin and insulin. We observed that systemic deletion of SH2B1 disrupts energy balance, resulting in severe obesity, type 2 diabetes, and fatty liver disease in mice. Deletion of SH2B1 specifically in leptin receptor-expressing neurons also results in obesity and obesity-associated metabolic disease. In line with these findings, restoration of SH2B1 in the brain of SH2B1-null mice is sufficient to rescue obesity phenotypes. GWAS studies reveal that SH2B1 single-nucleotide polymorphisms (SNPs) are associated with obesity, metabolic disease, and cardiovascular disease in humans. SH2B1 missense mutations are also linked to human obesity. Mechanistically, neuronal SH2B1 promotes weight loss at least in part by enhancing leptin and insulin action in the brain.
Xiang Gao, Ph.D.
Nanjing University, China
Xiang was the founder for both MARC and National Resource Center for Mutant Mice. He is awarded Professor of Cheung Kong Scholars by Ministry of Education in 2002. He is the recipient for the National Science Fund for Distinguished Young Scholars. Xiang currently service as the president of Asian Mouse Mutagenesis and Resource Association (AMMRA) and Director for Nanjing Biomedical Research Institute of Nanjing University (NBRI).
His laboratory is fascinated by the tight control of physiological homeostasis. Over the years, we have worked in this field with different organs, including regulation of bone mineral density regulation responded to mechanical force by sost1; maintenance of calcium and phosphate level by PHEX, establishing of skin immune privilege by Gsdma3, and sustain of glucose homeostasis after meal by Pax6-mediatd GLP-1 expression.
Control of one “simple” physiological process often involves many organs and gene functions. For instance, the glucose homeostasis is regulated by brain, muscle, liver, adipose tissue, gut and bones. Now we know the micro flora in gut also participates the metabolic control. And because of that, some of these regulation pathways may only be activated when the organism is challenged under specific environments or physiological stresses. Unfortunately, most of our experiments with live animals are carried out in a SPF facility therefore how to apply the challenge becomes a crucial issue.
Understanding the physiological homeostasis may also be tackled at difference stages, the establishment, maintenance, and reset of a specific physiological status. One of the projects in his lab is try to understand the obesity “memory”. It is commonly believed an obese person will obtain a tendency to get fatty again after losing weight by food restriction or excises. They confirmed this phenomenon using mouse models. The mice used to be fat gain body weight faster than the little mate control in both normal diet as well as high fat diet, suggesting a “memory” of old physiological status.
Finally, he should keep in mind of the interaction between different signaling pathways that control physiological regulation. Separated protein domains execute these cross-talks. By analyzing two mouse strains carrying different point mutations in c-Kit gene, he found they share the abnormalities in many cell types but display opposite phenotypes in myeloid tissue. Mutation in the first immunoglobulin-like domain of Kit leads to myeloproliferation, whereas the kinase-dead mutation leads to anemia. Detailed analysis revealed that KIT protein can physically interacts with the beta common (βc) receptor of the gp140 family through first Ig domain. And the mutation in this position of KIT activates the Epo-R and IL-7R in the absence of their ligands, Epo and IL-3, by facilitating the constitutive recruitment of JAK2 to Kit. Considering active mutations of the βc receptor lead to myeloproliferative neoplasms, it would be interesting to determine whether these mutations enhance the interaction with the Kit receptor to induce cytokine- independent proliferation.
The mystery of physiological homeostasis is just beginning to be understood. Careful studies will not only shed the light in the regulatory loops for the beauty of complicated life, but the potential cure for diseases resulting from disruption of these feedback loops.
The Stem cell factor/Kit signaling pathway regulates mitochondrial
function and energy expenditure
Cell growth is tightly coupled with mitochondrial biogenesis in order to maintain energy and organelle homeostasis. Receptor tyrosine kinase Kit and its ligand, stem cell factor (SCF), play a critical role in the growth and survival of multiple cell lineages. Here we report thatthe expression of SCF and Kit in adipose tissues is responsive to food availability and environmental temperature, and is altered in obese mice and human patients. Mice carrying a loss-of-function mutation in Kitdevelop obesity as a result of decreased energy expenditure.These phenotypes are associated with reduced PGC-1α expression and mitochondrial dysfunction in brown adipose tissue and skeletal muscle. We further demonstrate that SCF/Kit directly promotes Ppargc1a transcription and mitochondrial biogenesis. Blocking Kit signaling in mice decreases PGC-1α expression and thermogenesis, while overexpressing SCFsystemically or specifically in brown adipose tissueincreases thermogenesis andreduces weight gain. Collectively, these data provide mechanistic insight into the regulation of mitochondrial function by SCF/Kitsignaling and lay a foundation for exploring SCF/Kit signaling as a therapeutic target for metabolic diseases.
Yong Ji, M.D.,Ph.D.
Nanjing Medical University, China
Professor Yong Ji is the doctoral tutor in Nanjing Medical University. Yong got his clinical medicine degree from Nanjing Medical College in 1991, and Ph.D. degree of cardiovascular pharmacology from Nanjing Medical University in 1998. Granted by French Ministry of Science, Yong completed his postdoctoral research in French National Academy of Medical Sciences (INSERM U464), focusing on protein interactions. Then granted by Wellcome Trust funding, Yong worked as a research fellow in King’s College London, in UK, mainly studying the mechanism of eNOS in atherosclerosis, the vascular endothelium and platelet dysfunction in type 2 diabetes.
Yong went back to China in 2004 and served as a professor of Department of Pathology and Pathophysiology, Research Center of Atherosclerosis and Jiangsu Key Laboratory of Cardiovascular Molecular Intervention in Nanjing Medical University. The research team, led by Yong Ji, mainly work on gasotransmitter nitric oxide and hydrogen sulfide and their effect on various cardiovascular diseases, such as myocardial hypertrophy, myocardial ischemia-reperfusion injury, diabetes and atherosclerosis, as well as their mechanisms.
Yong has taken charge of multiple research projects, including beforehand research project of National Key Basic Research Program of China (973 Program), projects of National Natural Science Foundation of China (both the major and general projects). The research team has published over 50 research papers on international academic publications, such as Proc Natl Acad Sci USA, Cardiovasc Res, J Mol Cell Cardiol, Br J Pharmacol, etc.
Yong serves as vice chairman of Chinese Atherosclerosis Society of Chinese Association of Pathophysiology and editor of British Journal of Pharmacology.
Nitric oxide regulation and its role in cardiovascular system
The vascular endothelium produces a variety of vasoactive substances which have important effects on vascular tone, hemostasis, leukocyte and platelet adhesion, vascular permeability, and atherogenesis. One of the most important of these mediators is nitric oxide (NO). Nitric oxide plays important role in cardiovascular physiology and pathophysioloy. Our group found that the polymerization status of β-actin plays important role in maintaining the eNOS activity. The stimulating effect of eNOS agonists, such as collagen, thrombin, salbutamol and histamine, is dependent on its interaction with globular actin. Curative effects of many clinical drugs and compounds, such as aspirin, pyridoxine, and aliskiren, on cardiovascular disease, are dependent on their interaction with eNOS. Aspirin can acetylates NOS-3 acutely on both serine-765 and serine-771 and this causes an increase in its activity as well as a decrease in its phosphorylation on serine-1177; Pyridoxine (Vitamin B6) can prevent LDL-induced dysfunction of endothelial cell NO generation and improve the eNOS uncoupling in endothelial cells via PKCα pathway. Aliskiren, the first orally effective direct renin inhibitor to be used clinically, is cardioprotective in the context of myocardial ischemia reperfusion injury, predominantly through activation of the PI3K-Akt-eNOS pathway.
Qi Chen, Ph.D.
Nanjing Medical University, China
Chen Qi was graduated from Karl-Franzens University Graz with a Ph. D degree in Austria in 1993. He is a professor of pathophysiology of Nanjing Medical University.
Dr. Chen is interested in the research on mechanisms of cardiovascular diseases, which was supported by many national scientific grants. Parts of his research results were published in journals including Am J Resp Crit Care Med, Diabetes, ATVB, Diabetologia, JBC et al. At the moment he is also involved in social activities as China Pathophysiology Association, Heart Association, and Atherosclerosis Association.
Inflammation regulation in obese adipose tissue and vascular remodeling
Chronic low-grade inflammation, particularly in the adipose tissue, orchestrates obesity-induced insulin resistance and its complication. In this process, polarized activation of macrophages plays a crucial role. We investigated the role of Class A scavenger receptor (SR-A) in regulating macrophage polarization in obese adipose tissue and vascular remodeling. Our results showed that deletion of SR-A resulted in a reduced insulin sensitivity in obese mice and a marked augmentation of angiotensin II (Ang II)-induced hypertensive vascular remodeling. Therefore, SR-A may be a useful therapeutic target for the intervention of the obesity-induced insulin resistance and hypertensive vascular remodeling.
Yi Zhun Zhu, M.D.,Ph.D.
Fudan University, China
Dr. Yi Zhun Zhu got his M.D./Ph.D. at Faculty of Medicine, University of Heidelberg, Germany in 1995. He joined as a faculty member of the Department of Pharmacology, National University of Singapore (NUS) in 1998 after postdoc training at Kiel University and industrial experience at Hoechst Marion Roussel (now Sanofil). Dr. Zhu is currently a Professor of Pharmacology (part time as adj-professor at Pharmacology, NUS), Dean of School of Pharmacy and Director, Institute of Drug R&D, Fudan University. Dr. Zhu published more than 130 peer-reviewed papers with more than 2700 citations and edited 2 books for his work. He is an associate editor J Alzheimer Diseases, Life Sciences and editorial board member of Biosci. Reports. Dr. Zhu is also editor-in-chief for the national text book of Pharmacology (7th edition, People’s Medical Publishing House), Dr. Zhu was awarded ‘distinguished Young Scientist Grant from Natural Science Foundation of China (NSFC) in 2008 and Chief Scientist of National Key Research Program (973) and Chief-PI for the National Platform of Drug Discovery in 2009. Dr. Zhu further received National Award for Innovative Research Work of the Returnees in 2009 from State Council and Magnolia Award from Shanghai Government in 2010. Dr. Zhu was awarded 2011 Cheung Kong Professorship by the Ministry of Education, China. His research focuses on molecular pharmacology/drug mechanisms especially for heart and brain. Two novel compounds as drug candidates have been completed pre-clinical trials and are moving to clinical trails now.
Novel Compounds development for cardiovascular diseases and new mechanisms
H2S is the third physiologically relevant gaseous signaling molecule with a diverse physiological profile. The release of endogenous H2S from cells is likely to occur in lesser amounts and at a much slower rate than that from sulfide salts, which could not mimic the biological effects of naturally produced H2S. Therefore, modulation of endogenous H2S production may be of therapeutic benefit in cardiovascular and CNS diseases. A significant amount of effort is being channeled into developing novel therapeutics based ondeliveringH2S.We have identified that the salubrious effects of H2S may due to its various biological activities, such as anti-oxidation, anti-inflammation, and so on. Interestingly, our group also found that S-propargyl-cysteine (SPRC), a novel sulfur-containing amino acid, exerted neuroprotective and cardiovascular-protective effects in in vivo and in vitro studies through modulation of endogenous cystathionine γ-lyase (CSE)/H2S system.For example, we identified that SPRC or nano-preparation of SPRC was shown to preserve endogenous CSE/H2S levels and upregulated various anti-oxidative enzymes after myocardial infarction. In addition, SPRC also prevent against cytokine-mediated endothelial dysfunction. Furthermore, SPRC may attenuate inflammatory responses and spatial learning and memory impairment in bilateral intracerebroventricular LPS-injected rats, at least partly, by H2S-mediated pathway. More recently, we also demonstrated that SPRC could induced angiogenesis involved in a STAT3-dependent mechanism, which may be a potential therapeutic strategy for ischemic disease through angiogenesis promotion. Based on the above studies, SPRC has been already in pre-clinical studies. Taken together, these data suggest that SPRC, a novel endogenous H2S-modulated agent, can be used as a neuroprotective and cardiovascular- protective agent.
Y. Eugene Chen, M.D., Ph.D.
The University of Michigan Medical Center, USADr. Chen is the endowed Frederick Huetwell Professor of Cardiovascular Medicine, Director of the Center for Advanced Models for Translational Sciences and Therapeutics, and Vice-Chair for Basic and Translational Research at the Department of Cardiac Surgery at the University of Michigan Medical Center. The long-term goal of Dr. Chen’s research program in vascular medicine is elucidating the molecular basis of obesity/diabetes-induced cardiovascular diseases (CVD) and stroke, and on developing new drugs/technologies to study and treat diabetes and CVD. In the past years, Dr. Chen has made a series of significant contributions to our understanding of the role of PPAR activation as a determinant of vascular cell gene expression and cellular function and has been among the first to define the role of PPAR activation in the cardiovascular system. The discovery of the high affinity physiological PPAR ligands, nitro-fatty acids advances our understanding of endogenous PPAR modulation and provides novel therapeutic strategies for treating obesity/diabetes and CVD. Dr. Chen was the first one to clone the exendin-4 (BYETTA, the drug name for Exendin-4) gene in 1995.
Advancing Lipid GWAS Discoveries to Innovative Targets for CVD
Plasma lipid levels are the most important risk factors for coronary artery disease (CAD). Genome-wide association studies (GWAS), which involve genotyping hundreds of thousands of single nucleotide polymorphisms (SNPs) in thousands of individuals phenotyped for lipid traits, have evolved as an unbiased tool to identify common genetic variants that contribute in a causal manner to lipid variations in the population. The major challenge for a successful GWAS is applying the findings to accelerate drug and diagnostics development. To date, GWAS for plasma lipid levels have identified convincing association with more than 150 common genetic variants. Based on these premises, we recently examined several candidate genes. Our findings will provide novel potential targets for CAD treatments.
Alex F. Chen, Ph.D.
Central South University, China
Dr. Chen received his doctorate degree from Southern Illinois University School of Medicine and completed his NIH Postdoctoral Fellowship training at the Mayo Clinic, Rochester, Minnesota. Subsequently, Dr. Chen worked as an Assistant Professor (tenure-track) and Associate Professor (tenured) at Michigan State University, and Professor (tenured) in the Department of Surgery at University of Pittsburgh School of Medicine.
Dr. Chen has a long-standing interest in vascular biology related to hypertension and diabetic complications including wound healing and has performed these studies for more than 20 years. He has strong experience and publication record in endothelial cell biology and pathobiology. His laboratory has made several important contributions to our understanding of the regulation of oxidative stress in endothelial cell dysfunction.
Dr. Chen has mentored over 50 postdoctoral fellows, 10 Ph.D. students, 5 medical students, 17 undergraduate students and 2 residents. Two of his postdoctoral fellows are currently research faculty members at University of Pittsburgh School of Medicine. Many of his previously trained postdoctoral fellows now serve as full professors at their respective institutions in China, including the Peking University, Sun Yat-Sen University, The Third Military Medical University, Central South University, and the Second Military Medical University. Four of the undergraduate students who had worked in his lab have already been resident physicians in the US. The postdoctoral fellows in Dr. Chen’s lab have similarly distinguished themselves by obtaining 7 American Heart Association (AHA) Postdoctoral Fellowships. One of his M.D./Ph.D. students had also obtained the AHA Predoctoral Fellowship and another previous medical student had received an AHA Medical Student Scholarship. One of his research fellows has been awarded an AHA Scientist Development Grant (SDG).
MicroRNA Regulation of Endothelial Progenitor Cell Angiogenesis in Diabetes
Endothelial progenitor cells (EPCs) are a circulating, bone marrow-derived cell population that participates in both vasculogenesis and vascular homeostasis. Recent studies have shown that EPCs are reduced by ~50% in diabetes that correlates inversely with its mortality rate. In addition, EPC angiogenic functions are severely impaired in diabetes. However, the molecular and cellular mechanisms underlying EPC dysfunction are poorly understood. Our current studies have focused on in vitro and in vivo aspects of oxidative stress regulation of EPC dysfunction and angiogenesis in diabetes.
MicroRNAs (miRNAs) are endogenous non-coding RNAs that regulate gene expression at the posttranscriptional level. However, whether miRNAs regulate EPC-mediated angiogenesis in diabetes is unknown. Our experimental observations suggest that let-7f and mir-27b are two important pro-angiogenic miRNAs involved in the regulation of EPC-induced angiogenesis in diabetes via different pathways. Our latest findings will be presented, and they may provide a mechanistic basis for developing autologous cell-based therapies to combat EPC dysfunction in diabetes and other cardiovascular diseases.
Burns C. Blaxall, Ph.D., FAHA
Cincinnati Children’s Hospital Medical Center, USA
Burns C. Blaxall is a Professor of Pediatrics, Director of Translational Science in the Heart Institute at Cincinnati Children’s Hospital Medical Center. He received his Ph.D. in Pharmacology from the University of Colorado Health Sciences Center in Denver, Colorado and completed his postdoctoral fellowship at Duke University Medial Center in Durham, North Carolina. At the University of Rochester Medical Center and Aab Cardiovascular Research Institute, he directed the Howard Hughes Medical Institute Med-into-Grad Fellowship in Cardiovascular Science. Dr. Blaxall has received many academic honors, including the Early Career Investigator Award from the American Heart Association (AHA) in 2007, the Outstanding Achievement Award from the Founder’s AHA Affiliate in 2009 and the Merit Award for Research Achievement from Mended Hearts, Inc. in 2009. He is an elected Fellow of the American Heart Association and serves on multiple NIH peer-review panels for the National Heart, Lung and Blood Institute. He is currently a principal investigator (PI) for two R01 grants from NIH through 2015 as well as an AHA Innovative Research Grant. Dr. Blaxall’s lab has trained cardiology fellows, postdoctoral fellows, PhD and undergraduate students.
1) Molecular and signaling mechanisms of heart failure
2) Cardiac Fibrosis
3) Drug and therapeutic discovery
New approaches to an old disease: therapeutic discovery for heart failure
The authors propose simultaneous inhibition of Gβγ signaling in the heart and the adrenal gland as a novel therapeutic approach for heart failure (HF). Elevated sympathetic nervous system activity is a salient characteristic of HF progression. It causes pathologic desensitization of β-adrenergic receptors (β-AR), facilitated predominantly through Gβγ-mediated signaling. The adrenal glands are key contributors to the chronically elevated plasma catecholamine levels observed in HF, where adrenal α2-AR feedback inhibitory function is impaired also through Gβγ-mediated signaling. We investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant, pressure-overload model of HF. Daily galleon treatment (10 mg/kg/day), initiated 4 weeks after transverse aortic constriction, improved survival and cardiac function and attenuated cardiac remodeling. Mechanistically, gallein restored β-AR membrane density in cardiomyocytes, attenuated Gβγ-mediated G-protein-coupled receptor kinase 2-phosphoinositide 3-kinase γ membrane recruitment, and reduced Akt (protein kinase B) and glycogen synthase kinase 3β phosphorylation. Gallein also reduced circulating plasma catecholamine levels and catecholamine production in isolated mouse adrenal glands by restoring adrenal α 2-AR feedback inhibition. In human adrenal endocrine tumors (pheochromocytoma), gallein attenuated catecholamine secretion, as well as G-protein-coupled receptor kinase 2 expression and membrane translocation. These data suggest small molecule Gβγ inhibition as a systemic pharmacologic therapy for HF by simultaneously normalizing pathologic adrenergic/Gβγ signaling in both the heart and the adrenal gland. Our data also suggest important endocrine/cardiovascular interactions and a possible role for small molecule Gβγ inhibition in treating endocrine tumors such as pheochromocytoma, in addition to HF.
Jun Ren, M.D., Ph.D., FAHA
University of Wyoming, USA
Dr. Ren earned his Ph.D. in 1994 from the University of Alberta, Canada, in the area of cellular physiology, following his medical training in China (Beijing University and Peking Union Medical College). In 1994, he became a post-doctoral fellow in the Wayne State University School of Medicine (Internal Medicine), where he served for two years. He remained at Wayne State University until 1998, working as a research instructor of physiology. He was an Assistant Professor of Physiology at the University of North Dakota School of Medicine and Health Sciences from 1998-2002 and then an Associate Professor of University of Wyoming from 2002-2005. He was promoted to full professor in 2005 and was appointed as Associate Dean for Research in the College of Health Sciences at the University of Wyoming. His major area of research is related to cardiac pathophysiology in alcoholism, diabetes, obesity and aging. His research has been funded by the American Heart Association, American Diabetes Association and NIH. He is a first or corresponding author of more than 450 peer-reviewed papers and 100 published abstracts. He is editor or on editorial board for a number of journals including Diabetes, Journal of Molecular and Cellular Cardiology, American Journal of Physiology, Cardiovascular Toxicology and Clinical and Experimental Pharmacology and Physiology.
Qinglin Yang, Ph.D.
University of Alabama at Birmingham, USA
Dr. Qinglin Yang is a full Professor with tenure and senior scientist from the University of Alabama at Birmingham (UAB), AL, USA. Dr. Yang received his bachelor and master of medicine degrees from Guang Zhou University of Chinese Medicine in Guang Zhou, China in 1984 and 1989, respectively. From 1991 to 1996, he obtained his Master degree (Pharmacy) from the University of Montana of USA and his PhD degree (Cardiovascular Physiology) from Washington State University of USA. After 4 years of postdoctoral training at Cincinnati Children's Hospital Medical Center, Dr. Yang established his lab within the Cardiovascular Research Institute of Morehouse School of Medicine in Atlanta. In 2008, he moved his research team to UAB. Dr. Yang's lab focuses on exploring metabolic mechanisms underlying the development and progression of heart failure, especially those related to transcriptional regulation of myocardial fatty acid and carbohydrate metabolisms (eg., PPAR signaling pathway) in pathological conditions such as hypertension, obesity and diabetes. His lab uses cutting-edge technologies in molecular genetics, molecular and cellular biology, biochemistry and Pathophysiology to identify mechanisms and get insights into novel therapeutic strategies. Dr. Yang has won several academic and service awards over his career, including the Outstanding Early-career Investigator Award from the Council on Basic Cardiovascular Sciences of American Heart Association (2004); the distinguished service award from Academy of Cardiovascular Research Excellence (ACRE) (2012) and the distinguished Scholarship Award for Research, from the School of Health Professions at the University of Alabama at Birmingham. Dr. Yang has published over 60 peer reviewed papers including several in top journals such as Nature Medicine, Journal of Clinical Investigation, Circulation and Circulation Research. He has served as grant reviewer for funding agencies such as NIH, AHA, ADA, Welcome Trust, Italian Ministry of Health, Swiss National Science Foundation and Latvian Science Council. Dr. Yang routinely reviews manuscripts for main academic journals and currently serves as editorial board members for 7 scientific journals such as Diabetes, PPAR Research and BioMed Research International.
Energy metabolism regulation and cardiac disorders
Myocardial energy metabolism plays a pivotal role in maintaining normal cardiac function and protecting the heart from pathological stress. Numerous studies in the last half-century demonstrate that myocardial energy deficiency is a common feature among a variety of cardiac disorders. Improving myocardial energetic state has been attributed to the beneficial effects of current therapies for the treatment of heart failure. However, direct interventions optimizing myocardial energetic state remain scarce. Multiple layers of regulations of myocardial energy metabolism have been illustrated. Deficiencies at many of these regulation mechanisms can lead to cardiac dysfunction. In addition to identifying key transcriptional regulators of myocardial energy metabolism, we have recently focused on defining key mechanisms underlying the biochemical control of myocardial energy metabolism. Specifically, we have investigated ATP synthase interacting proteins that are involved in the control of this molecular motor, as key regulating mechanisms of energy metabolism using in vitro and in vivo approaches. We have also investigated the subsequent impacts of manipulating this key ATP producing step on important pathological processes of the heart under pathological stress conditions. Results from our studies suggest that understanding of the regulation the ATP synthase may help identify effective therapeutic target for the treatment of cardiomyopathy and other heart diseases.
Xin Wang, Ph.D.
University of Manchester, UK
After the first degree in Bachelor of Medicine (Hubei Medical University, 1990), I steered my career path to Medical Sciences and underwent rigorous research training in the labs of David Garrod and Cathy Tournier in the field of call signaling in Physiology and Disease. On completion of my Ph.D. and Postdoc training in UK (University of Manchester), I was awarded a prestige fellowship by Research Council UK (RCUK) in 2006, which enabled me to establish independent research in cardiac signaling regulation. Since then I have been promoted to University Lecturer, Senior Lecturer, and Director of Cardiovascular and Metabolic Disease Research Theme. My main research interest lies in cell signaling and gene regulation underpinning genesis of cardiac disease. Complementary approaches combining animal models, human iPS cell system and computer simulation empower my group to study pathological mechanisms and identify potential new treatment options for heart failure and cardiac sudden death, aging associated atrial fibrillation, and metabolic disorders associated cardiomyopathy. Over the past several years, many important works from my group have been published in leading journals, highlighted by the recent study on Pak1 in cardiac hypertrophy, which has been selected as one of the most important and most read papers by Circulation for 2012. My research is generously supported by British Heart foundation (BHF), Medical Research Council (MRC) and various Industrial funding over £1.97 millions since 2007.
Sitting in a number of committees of British Pharmacological Society, I have been actively involving in conference organisation, promoting scientific collaborations within UK, between UK and China, and worldwide. As an editor of British Journal of Pharmacology (BJP), I have been endeavouring to recruit top pharmacological papers, and increase BJP recognition in China through a range of theme issues. Meanwhile, I have been working in reviewing panels for funding bodies, such as BHF, MRC, Biotechnology and Biological Sciences Research Council (BBSRC), Austria Science Foundation and Israel Science Foundation, and undertaking an honour position in Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, and chief scientific consultant of Kanion Pharmaceuticals Co.
A novel mechanism of epigenetic regulation of potassium channels
and cardiac repolarisation
Over half of heart failure patients die of arrhythmic death, which claims about 20% of total mortalities worldwide, and 100,000 lives a year in UK, more than breast cancer, lung cancer and AIDS combined. Current anti-arrhythmic agents are designed to block ion channel activity, which can cause pro-arrhythmic effects, culminating in greater overall mortality risk. Our current work provides important evidence supporting an emerging concept by targeting “upstream regulators” of ion channels as a new treatment route against ventricular arrhythmias. We recently discovered a novel mechanism underlying gene regulation of a set of potassium (K+) channels through a signaling complex comprised of mitogen-activated kinase kinase 7 (MKK7), histone deacetylase (HDAC) and Krϋppel-like factor (KLF). Gain and loss of function studies demonstrate a critical link of stress signaling pathways through the MKK7/HDAC/KLF mechanism with repression of cardiac K+ channels, repolarisation delay and susceptibility to arrhythmias. Our data in an arrhythmic mouse model further reveal the effect of HDAC inhibition by pharmacological inhibitors on restoring K+ activity and reducing arrhythmic propensity. This study suggests a gene regulatory avenue for treatment of cardiac arrhythmias.
Xian Wang, Ph.D.
Peking University, China
Prof. Xian Wang. Cheung Kong Professor in Physiology; Director of Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education; Vice Principal of Peking University Health Science Center; Vice President of Chinese Association for Physiological Sciences (CAPS).
Prof. Wang’s major research interest is related to the pathogenesis and prevention of metabolic vascular diseases. She has been the recipient of many awards and honors during her career, such as “Distinguished Young Investigator Award” honored by the National Natural Science Foundation of China, Leader of “Innovation Research Groups of NSFC” and so on. Over a decade, she has received more than 30 national research grants to support her research and published more than 170 scientific papers, 120 papers of which have been published in SCI journals, such as Circ Res, Diabetes, Am J Physiol and FASEB J. etc.
Feng Gao, M.D., Ph.D., FAHA
The Fourth Military Medical University, China
Dr. Feng Gao is a Professor of Physiology, Associate Dean of the School of Basic Medical Sciences at the Fourth Military Medical University, Xi’an China. He also holds positions as Adjunct Professor at Thomas Jefferson University and Adjunct Professor at Peking University. He received his MD and PhD of Physiology from the Fourth Military Medical University and had his postdoctoral training at Thomas Jefferson University.
Dr. Gao has been engaged in the field of cardiovascular physiology with focus on cardioprotection for many years. His first major finding at the early stage of his academic career in 1999 is the cardioprotective effect of postconditioning for the ischemic/reperfused heart. In the face of the ever-growing population of diabetic patients in China and in the world and the increased risk of cardiovascular complications in diabetes, he has devoted himself to the study on the role of insulin in cardiovascular health and disease. His lab found that insulin exerts significant antiapoptotic and cardioprotective effects via activating the cardiac endogenous eNOS-NO system through PI3 kinase-Akt signaling mechanism. Based on these findings, they proposed the “insulin hypothesis” in early 2000s which highlighted insulin as the predominant protective component in the GIK regimen, and was afterwards verified by a series of clinical and experiment studies. This insulin-induced “survival” signaling and resultant cardioprotection may represent a novel approach for the development of pharmacological strategies that prevent insulin resistance and attenuate reperfusion myocardial injury, especially in diabetics. Currently, his lab is studying the role of mitochondria in exercise-induced cardioprotection in diabetic cardiovascular diseases. These findings have been published in Circulation, Am J Physiol, and Cardiovasc Res have been widely cited over 2300 times.
He has served as Editorial Board Member of Cardiovasc Res, Apoptosis, and Am J Physiol Heart Circ Physio, and Associate Editor of Life Sciences, Executive Associate-Editor-in- Chief of Acta Physiologica Sinica and Chinese Heart J.
Rutai Hui, M.D., Ph.D.
Peking Union Medical College, China
Dr.Hui got his Ph.D. from University of Montreal, Canada. Subsequently, he was trained as a postdoc fellow in NIH. From 1997, as the director of Sino-German Laboratory for Molecular Medicine in Fuwai Hospital, he focused on clinical cardiovascular genetics. Recently, Dr. Hui’s group determined several novel genes involved in cardiovascular disease (MCR2005, Circ. Res 2010, Hum Mol Genet 2010), firstly reported the de novo frame shift mutation of the γ-subunit causing Liddle syndrome(ClinEndocrinol 2007), and the mutations in NEXN involved in the pathogenesis of HCM(Am J Hum Genet 2010), and firstly demonstrated the link between vitamin K and arterial vascular wall by VKORC1 (Circulation 2006, Cir: Cardiovasc Genet 2013, Hum Genet 2013). And also, his group did lots work in cardiovascular disease susceptibility genes (JACC 2007, Hypertension 2009, Stroke 2005&2009&2011&2012) and pathology of atherosclerosis (ATVB 2013). Dr. Fan serves as an ISHR president in China, and Editor in Chief of Molecular Cardiology of China, and the vice director of the State Key Laboratory of Cardiovascular Disease.
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China principal research interests: Cardiovascular Genetics, genomics and epigenetics, mainly focus on high blood pressure, atherosclerosis and cardiomyopathy.
Zhiming Zhu, M.D.
Third Military Medical University, China.
Dr. Zhu received his medical degree in 1985 and Master of Science in Cardiology from the Third Military Medical University, Chongqing in 1988 and obtained his M.D. from Muenster University, Germany in 1993. He received postdoctoral training and as a research associate at Department of Cell Biology and Physiology in University of North Carolina at Chapel Hill from 1994-1997. He is a visiting professor in Riley Heart Research Center, School of Medicine, Indiana University-Purdue University Indianapolis from April to November, 2002.
Dr. Zhu’s research interests focus on: mechanism and treatment of hypertension and metabolic syndrome. Of special interest is the role of transient receptor potential (TRP) channels in the pathogenesis of cardiometabolic diseases. He is a fellow of AHA and member of ISH. He is chief scientist of national basic research program on hypertension research in China. He was selected as changjiang scholar and national science found for distinguished young scholars of China. He has published over 70 peer-reviewed articles such as Cell Metabo, Circ Res, Hypertension, ATVB, Stroke, Diabetes, Cell Res, JAHA, et al. He serves on the Editorial Board of Clinical Science, Pflugers Archiv, Hypertension Research, PloS One (Academic Editor), and on more than ten editorial boards of Chinese professional journals including Chin J Hypertension (Deputy Editor).
Zhiren Zhang, M.D., Ph.D.
Harbin Medical University, China
Zhi-Ren Zhang received his M.D. and Ph.D. respectively from Harbin Medical University and Semmelweis University. He completed his postdoctoral training at the Department of Physiology School of Medicine, Emory University on Dec. 30, 2000. He worked as a senior scientist at the School of Biology, Georgia Institute of Technology from Jan 1, 2001 - June 30, 2005. He was appointed as a Tenure Track Assistant Professor at the Department of Medicine, Medical University of South Carolina on July 2005.
Since July 1, 2008, Zhi-Ren Zhang has been the Dean of Institute of Clinical Pharmacology at Harbin Medical University, the Co-Chair of Department of Cardiology at the 2nd Affiliated Hospital of Harbin Medical University. He is also the Co-Director of Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, at Harbin Medical University.
Zhi-Ren Zhang has longstanding research interest in understanding the mechanism and regulation of ion channels and transporters, and how these processes are affected in human diseases, such as hypertension and arrhythmia. He has published more than 40 peer-reviewed research articles.
Jingsong Ou, M.D, Ph.D.
The First Affiliated Hospital of Sun Yat-sen University, China
Jing-song Ou, M.D, Ph.D. the Pear River Scholar Professor and Associate Chief of Division of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University and the Vice Director of Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases. He got a Distinguished Young Award from National Natural Science Foundation of China in 2013. He was graduated from Cardiothoracic Surgery of Sun Yat-sen University of Medical Sciences in 2000. From 2000 to 2001, he was trained in Cardiothoracic Surgery of University of California-Los Angeles. He did his postdoctoral training in Medical College of Wisconsin from 2001 to 2003. In 2005, he became an assistant professor in Department of Surgery in Medical College of Wisconsin and returned to China in 2007. He is an editorial board member in American Journal of Physiology-Endocrinology and Metabolism. He has carried out a series of studies on the mechanism of endothelial nitric oxide synthase regulation, and its effect on perioperative cardiovascular protection as well as its clinical application. He also studies the relationship between high density lipoprotein dysfunction and cardiovascular diseases as well as cardiac surgery. He has published more than 30 papers at SCI journals, including Circulation, Circulation Research, Arteriosclerosis, Thrombosis, and Vascular Biology, Journal of Molecular and Cellular Cardiology, The Journal of Thoracic and Cardiovascular Surgery. Among them, 16 papers are correspondence authors’ and the impact factor of 3 papers is more than 16 respectively. These papers have been cited more than 700 times.
Ben He, M.D,Ph.D.,FACC
Shanghai Jiao Tong University, China
Prof. Ben is the Director of Cardiovascular department, Renji Hospital affiliated to Shanghai Jiaotong University.
He started his medical career in 1985. He got his M.D./Ph.D. degree from Shanghai Jiaotong University, School of Medicine in 1993 and was well trained in cardiology during his early medical period. He is one of the earlier interventional cardiologist in China. In 2003, Prof. He was appointed as current position and he is expertise not only in complex coronary intervention but also in clinical cardiology. He is invited by TCT, Euro-PCR and CCT as international faculty in recent years. He and his group were actively involved in many famous clinical trials such as PLATO, OASIS-6 and ATLAS ACS 2-TIMI 51. Prof. He is also a physician scientist and pays much attention to academic research. His major investigatory interests focus on nuclear receptor and cardiovascular regulations, including prevention of ischemic/reperfusion myocardial injury and atherosclerosis plaque rupture and inflammation. He has published more than 50 clinical and scientific papers in peer-review SCI journal as corresponding author in recent years. He got the honor of “Top 10 best doctors of Shanghai” in 2012.
Huazhong University of Science and Technology, China
Prof. Kai Huang: Vice President for Union Hospital, Huazhong University of Science and Technology (HUST); Director of Clinical Center for Human Genomic Research, Union Hospital, HUST; Professor in Department of Cardiovascular Diseases, Union Hospital, HUST. Prof. Huang engages in research field of molecular cardiology. His main research interest is the transcriptional regulatory mechanisms of cardiovascular and metabolic diseases. He has received about 20 research projects from the National Natural Science Foundation, the Provincial Natural Science Fund and other scientific and technological programs to support his research. Prof. Huang has published more than 40 scientific papers, most of which have been published in SCI journals.
Wei Kong, M.D, Ph.D.
Peking University Health Science Center, China
Dr. Wei Kong is a professor of Physiology at Peking University Health Science Center. She earned her MD and Ph.D degree at Tongji Medical University, Wuhan, China. She pursued her postdoctoral training in University of Washington, Seattle and New York University from 2001 to 2005. She was appointed professor in Peking University in 2010 and awarded China National Funds for Distinguished Young Scientists in 2012. In the past 5 years, she has published 30 peer-reviewed papers in highly impacted scientific journals including Circ Res, Arterioscler Thromb Vasc Biol, Basic Res Cardiol, J Mol Cell Cardiol. Her research was funded by National Natural Science Foundation of International Cooperation, Ministry of Science and Technology "973" projects and Ministry of Education in China. She has severed as editorial board member of “Curr Vasc Pharmacol”. She research interest has focused on extracellular matrix remodeling during the pathogenesis of cardiovascular disease especially vascular calcification and abdominal aortic aneurysm. One of her major finding is identifying cartilage oligomeric matrix protein (COMP) as essential modulator for maintaining the homeostasis of cardiovascular system via several binding partners. She also characterizes a metalloproteinase ADAMTS-7, through COMP-degradation or COMP independent role, mediates vascular remodeling upon injury. The long-term goal of her study is to understand the cardiovascular matrix protein, as well as their proteinase and degradation fragments in the pathogenesis, diagnosis and prevention of cardiovascular disease.
Qing Jing, Ph.D.
Chinese Academy of Sciences, China
Qing Jing is a Professor and Principal Investigator of Institute of health Sciences, SIBS, CAS. He graduated from Second Military Medical University Shanghai and then received Post-doctoral training in Shanghai Institute of Cell Biology, CAS, China and Scripps Research Institute, CA. Dr. Jing received funds from National Natural Science Fundation of China, Ministry of Science and Technology of China, and Chinese Academy of Sciences. Several PhD students trained in Jing research lab have been accepted as post-doctoral fellows in U.S. renowned institutes such as the Gladstone and the Stowers Institute.
Professional Organizations: Fellow of American Heart Association (FAHA, 2012-).
1. Identification of tissue- and cell-specific MicroRNAs in cardiovascular systems and their physiological, pathological significance.
2. Regulation on differentiation of embryonic stem cells to cardiomyocytes, endothelial cells.
3. Lipid metabolism and molecular mechanism of atherosclerosis.
Kaichun Wu, M.D., Ph.D.
The Fourth Military Medical University, China
Dr. Kai Chun Wu is a professor and the Deputy Chair of Xijing Hospital of Digestive Diseases, The Fourth Military Medical University. He also serves as Vice-President of Chinese Society of Gastroenterology. He reveived his M.D. and Ph.D. degrees from the Fourth Military Medical University, and research experience in Oxford University, Nottingham University and Northwestern University.
Professor Wu's research focuses on tumor microenvironment and inflammation-related cancer metastasis. He first demonstrated that Forkhead box proteins play important roles in promoting HCC metastasis. His group found that FoxQ1 expression in HCC cells promotes the recruitment of macrophage infiltration through the VersicanV1/CCL2 axis, which in turn promotes HCC metastasis. These studies demonstrated that the crosstalk between HCC cells and tumor-associated macrophages play an important role in promoting HCC malignant progression and metastasis. In addition, his group found that overexpression of FoxC1 in HCC is a strong indicator of more aggressive tumors and poor clinical outcome. FoxC1 promotes HCC metastasis not only through the induction of EMT but also through upregulation of the adhesive molecule NEDD9. As a corresponding author, Professor Wu has published papers in Hepatology, J Hepatol, Oncogene, J Immunol, FASEB J, Carcinogenesis, Mol Cancer Res, etc.
He has a wide spectrum of research exposure and interest which includes inflammatory bowel disease, gastrointestinal tumor, gastroesophageal reflux disease, gastrointestinal bleeding, etc.
Gastric cancer-from bench to bedside
Gastric cancer remains a global public health problem, with over 70% of new cases and deaths occur in developing countries. H. pylori is considered as class I carcinogen for gastric cancer. Patients continue to have poor clinical outcomes as a result of late diagnosis and lack of effective treatment remain a major challenge. With rapid progress in molecular profiling of tumors and research in gastric cancer biology, a number of candidate biomarkers have been identified and validated for molecular classification. Molecular pathological classification plays increasingly important roles, including cancer surveillance/screening, diagnosis/staging, treatment and prognosis. Studies that clinically validated novel biomarkers and targeted therapies have provided insight into the diagnosis and treatment of gastric cancer. The gastric carcinoma-associated antigen MG7-Ag is a sensitive serum biomarker and may have a potential for gastric cancer screening in high-risk populations. The use of an immune-PCR or bio-plex technique can further increase its specificity and sensitivity for gastric cancer. When labeled with fluorescent agents, the MG7 antibody showed positive fluorescent staining in most gastric cancer samples and weak or no signal in noncancerous tissue samples, providing real-time imaging using confocal laser endomicroscopy. Considerable progress has been made in understanding the role of H. pylori in gastric cancer by a series of population-based studies in well-established high-risk areas. Studies that investigate the cancer malignant phenotypes have promoted understanding of gastric cancer and discovery of therapeutic targets. The success of the ToGA trial opened a new era for targeted therapy in gastric cancer. Trastuzumab, a monoclonal antibody against HER2, improved overall survival compared with chemotherapy alone in patients with the overexpression or amplification of HER2.
Peifeng Li, M.D, Ph.D.
Qingdao University, China
Prof. Peifeng Li was appointed as a member of “Program of One Hundred Talents of Chinese Academy of Science” in 2005. He was awarded Ph.D. by the Academy of Military Medical Sciences in 1993. From 1995 to 2005, Dr. Li was a medical researcher in the Max-Delbruck-Center for Molecular Medicine, Germany, studying apoptosis in cardiovascular disease. His original research sets up a relationship between cell apoptosis and cardiovascular disease, and opens up a new research area. Since 2005, Dr. Li became a professor in Institute of Zoology, studying the molecular mechanism of cardiac disease. His particular interest is in the function of mitochondria in cardiac diseases and the role of non-coding RNAs in the pathophysiological processes of the disease. His lab has established a fully functional platform for the generation and phenotyping of transgenic and knockout mouse models. Dr. Li has published over 70 papers in high level scientific journals such as Nature Medicine, Circulation, EMBO J, Molecular Cell, MCB, JBC, Cancer Research et al. Since 2014, he is the director of Institute for Translational Medicine, Qingdao University.
His research interests include cardiomyocyte apoptosis and regeneration, bological functions of non-coding RNAs in cardiovascular diseases, and heart failure.
microRNAs control mitochondrial dynamics of cardiomyocytes
Apoptosis can occur in the myocardium under a variety of pathological conditions. For example, myocyte apoptosis is increased in myocardium from patients with myocardial infarction and heart failure, and from experimental models of hypertrophy and heart failure. It plays a driving role in the transition from compensated hypertrophy to failure in the work-overloaded myocardium. Mitochondrial morphology is an important determinant of mitochondrial function. Mitochondria constantly undergo fusion and fission that are necessary for the maintenance of organelle fidelity. However, abnormal mitochondrial fusion and fission participate in the regulation of apoptosis. Mitochondrial fusion is able to inhibit apoptosis, while mitochondrial fission is involved in the initiation of apoptosis. Our data show that modulations of miR-499 levels can influence apoptosis, myocardial infarction and cardiac remodeling. Both the alpha- and beta-isoforms of calcineurin catalytic subunit are the targets of miR-499. Calcineurin dephosphorylates dynamin-related protein-1 (Drp1) leading to its accumulation in mitochondria, the activation of the mitochondrial fission program and the consequent apoptosis. miR-499 can regulate Drp1 phosphorylation status and mitochondrial fission through targeting calcineurin. Finally, p53 is shown to transcriptionally downregulate miR-499 expression. Our data provide novel evidence suggesting that miR-499 is a regulator of mitochondrial fission machinery, and the therapeutic approaches for myocardial infarction can be developed by modulating miR-499.
Hong Yuan, M.D., Ph.D.
Central South University, China
Dr. Hong Yuan is a Professor of Cardiology and Pharmacology, Director of Clinical Pharmacology Center, Vice Director of Cardiology and Vice President of the Third Xiangya Hospital at the Central South University, Changsha China. He is also the Fellow of American College of Cardiology (FACC), member of the International Society of Hypertension(ISH), Fellow of College of the Asian Pacific Society of Cardiology, and holds positions as Vice Chair at Hunan Cardiovascular Association and Vice Chair of Hunan Clinical Pharmacological Division. He received his M.D. and Ph.D. in the field of Cardiology from the Central South University, and furthered his research work as a visiting professor at the State Key Lab of Virus Genetic Engineering.
Dr. Yuan has been engaged in the field of Cardiology and Cardiovascular Pharmacology for almost 30 years, and dedicated his team to focus on mechanisms and clinical pharmacology of hypertension. His first major finding at the early stage of his academic career is the mechanisms of differences of antihypertensive efficacy between individuals. His group found that the gene polymorphisms and methylation of some drug receptors and metabolism enzyme receptors play vital roles in explaining the differences of antihypertensive efficacy. Based on these findings, they proposed the “gene-oriented individualized treatment of hypertension” in early 2000s which highlighted the importance of gene polymorphisms and methylation of β1-AR、CY2PD6、CYP3A4 and CYP3A5 in guiding the individualized treatment of hypertension. As the growing number of hypertension patients combined with renal dysfunction in the world, considering the poor blood pressure control rate and the serious consequences of complications induced by immune inhibitors in these patients after renal transplant, he has devoted himself to the study of the optimized antihypertensive treatment for these patients. His lab found that dose adjustment of tacrolimus should be considered according to CYP3A5 gene polymorphism when tacrolimus is coadministered with amlodipine and they build the quantitative pharmacology model and clinical database of hypertensive patients with renal damage, which may provide the theoretical basis and clinical data for further development of therapeutic drug monitoring and individualized therapy for hypertension. In addition, through many years of research on senile hypertension, he proposed some related risk factors for elderly hypertensive patients, such as fibrinolysis, platelet activation, inflammation, damage of endothelial function, hormone changes after menopause, which have the guiding significance to recognize the characteristics of senile hypertension. Currently, his team is focused on the following aspects: 1.optimization of antihypertensive treatment of hypertension in special populations; 2.exploration of early indicators and development of warning system for hypertension patients with target organ damage; 3.the role of high mobility group box-B1 (HMGB) in the pathogenesis of hypertension, carotid artery stenosis and pulmonary hypertension. These findings have been published in Hypertension, Journal of human hypertension, Drug Metabolism and Pharmacokinetics, J Cardiovasc Pharmacol and have been widely cited.
Dr. Yuan is a renowned cardiovascular specialist in China. He took charge of more than 40 research projects and 6 of them are funded by the National Natural Science Foundation, the National Science and Technology Major Projects for "Major New Drugs Innovation and Development", the National Key Technology R&D Program and the National Basic Research Program of China. He also presided or participated over 30 clinical trials, including 3 international multi-center studies. In the course of his career, he has published more than 250 articles as primary or co-author, issued 40 books, attained 15 awards and 7 national invention patents.
He teaches internal medicine and cardiovascular pharmacology at undergraduate and graduate levels. He has mentored 74 graduate students for their master’s or PhD degrees and currently 18 graduate students are studying under his mentorship.
He has served as Editorial Board Member of CNS Neurosciences Therapeutics, JACC (Chinese version), Chinese Journal of hypertension, Journal of Clinical Cardiovascular Disease, Journal of Chinese General Practice and Chin J Biochem Pharmaceutics.
Jiajun Zhao, M.D., Ph.D.
Shandong University, China
Dr.Zhao Jiajun is the director and professor of Department of Endocrinology and Metabolism, the head of Institute of Endocrinology and Metabolism in Shandong Academy of Clinical Medicine, the Vice President of Provincial Hospital affiliated to Shandong University, Jinan, China. He received his M.D. and Ph.D. from Shanghai Second Medical University. Dr. Zhao has received more than 20 grants and published more than 300 scientific papers in peer-reviewed journals. He is tutorial teacher in Endocrinology for the postgraduate students of Shandong University. Dr. Zhao's research has focused on the lipids effects of subclinical thyroid disease and type 2 diabetes. He is the corresponding author of numerous papers that appeared in such journals as Journal of Clinical Endocrinology and Metabolism, Endocrinology, Hepatology, J Hepatology, Clinical Endocrinology, Endocrine, European Journal of Endocrinology, etc.
Chairman, Shandong Diabetes Society
Chairman, Shandong Integrated Traditional and Western Medicine Association
Vice-Chairman, Chinese Endocrine Society
Ying Yu, M.D., Ph.D.
Chinese Academy of Sciences, China
Dr. Yu received his Bachelor degree from Medical college of Nanchang University in 1995, then got his Master degree in Tumor Immunology Department in the Medical College in 1998 and his PhD in tumor genetics from Cancer Research Institute in Xiangya Medical School in Central South University in 2001. He had his postdoctoral training in Pharmacology Department at University of Pennsylvania from 2002 to 2006, and then worked as Research Associate (2006) and Research Assistant Professor (2009) in the Institution for Translational Medicine and Therapeutics at University of Pennsylvania. He joined the Institute of Nutritional Sciences in 2009.
Dr. Yu has been engaged in studying cyclooxygenases (COXs) and their down-stream pathways involved in inflammatory response and cardiovascular diseases over 14 years. During the past several years, his work revealed the molecular mechanisms for COX-2 derived prostanglandin E2 (PGE2) involvement in injury-induced arterial remodeling; and found the unique role of COX-2 in blood pressure regulation and thrombogenesis; discovered COX downstream PGE2 receptor-EP3 mediates pulmonary vascular remodeling in pulmonary hypertension thorugh Rho/TGFβ1 signaling pathway; uncovered the underlying mechanisms for COX-1 derived PGE2 in the pathogenesis of aspirin intolerant asthma, discovered the mechanism for regulation of vitamin D on COX-2 expression in macrophage; found COX-1 derived thromboxane A2 (TxA2) is required for B cell development; and also revealed COX-derived PGI2 in hepetocytes promotes gluconeogenesis response to fasting. These works was published in Nat Med, Sci Transl Med. J Clin Invest. Circ Res, J Allergy Clinc Immunol, Diabetes, Blood, J Biol Chem at al.
Currently, research efforts in Dr. Yu’s laboratory are mainly focused on: i) COX, Ω－3 fatty acid, PGs in cardiovascular remodeling; 2) PG and their receptors in metabolic disorders and related vascular complications; 3) Food contamination and cardiovascular toxicity.
Ling Tao, Ph.D.
The Fourth Military Medical University, China
Dr. Ling Tao is currently a Vice Chief and Chief Physician in the Department of Cardiology of Xijing Hospital, a Professor of Medicine at the Fourth Military Medical University. Dr. Tao received his Ph. D in physiology from FMMU while she received her Ph. D trainning and post-doctoral training in the Department of Emergency Medicine of Thomas Jefferson University in the USA. Dr. Tao’s expertise includes basic research and clinical translational work in myocardial damage and protection of ischemic heart disease. Dr. Tao received the Junior Faculty Award from American Diabetes Association and the Best Oral Presentation Award at the 1st TJU Translational Medicine Annual Meeting in 2006. She received the First Prize of National Science and Technological Progress as the fourth accomplisher in 2011. In the same year, she also received Outstanding Abstract Award from American Heart Association, as well as Interventional Cardiology Young Pioneer Award. In 2012, she was awarded Chinese National Science Fund for Distinguished Young Scholars as well as New Century Excellent Talents in University. Dr. Tao currently serves in the editorial board of Journal of Cardiology & Clinical Research and Chinese Heart Journal etc. She is also reviewer of 18 SCI journals such as Diabetes. Dr. Tao has published 61 peer-reviewed manuscripts in many top ranked scientific journals, including Circulation, Circulation Research, Crit Care Med, PNAS, Diabetes, Antioxid Redox Signal, Basic Research in Cardiology. In addition, she holds three national patents for invention or utility model. Dr. Tao is currently serving as principal investigator for more than ten research grants including three Chinese National “Significant New Drug Development” programs, one Program for Chinese National Science Fund for Distinguished Young Scholars, one “863” Program, one “973” Program (sub project) and three Chinese National Science Funds. Dr. Tao is a committee member for AHA, ADA, Basic Science Committee of the Chinese Medical Association of Cardiology, and Hypertension and Vascular Disease Committee of the Chinese Medical Association. She is also a member for Committee of Cardiovascular Specialty of The PLA. In addition, she is a member of the leadership committee for the Great Wall International Congress of Cardiology and the executive chairman of the Basic Research Forum.
Xi-Yong Yu, M.D., Ph.D.
South China University of Technology Medical College, China
Prof. Yu is Senior Scientist and Professor in Guangdong General Hospital. Now, He serves a number of academic positions: Chairman of the Chinese Association of Pathophysiology Cardiovascular Society, Vice President of International Society for Heart Research China Section, the council member of Chinese Medical Association Cardiovascular Basic Study Group; President of Guangdong Provincial Pharmacological Society, the council member of Chinese Pharmacological Society, the standing members of Chinese Pharmacological Society Clinical Pharmacology Committee and Cardiovascular Pharmacology Committee; the Consulting Group Member of National Key Basic Research Program (973 program) of China in Health Sciences, the Final Review Expert of National Natural Science Fund Committee of China, the National GCP inspection group of senior expert. In addition, he also serves as the journal Editor of "Experimental Physiology" and the journal Regional Editor of "Current Cardiology Reviews".
Prof. Yu dedicated to cardiovascular basic and translational medicine research, specially focus on molecular cardiology and clinical pharmacology. The main research direction includes three aspects: ①stem cell research and tissue engineering regeneration in cardiac development and heart failure; ②regulatory mechanism of inflammatory stress on cardiovascular remodeling; ③pharmacoepigenetics of cardiovascular drugs in clinical trials. Total 400 academic papers, including 80 SCI papers, have been published related to the above research work. The published papers were cited by peers with total number of more than 1,000 times. He finished more than 40 human bioequivalence and pharmacokinetic studies of new drugs in clinical pharmacology, has undertaken 6 projects of National Natural Science Foundation of China (including 2 key programs), 1 project of National Key Basic Research Program of China (973 program), 3 projects of Ministry of Health Research Foundation, more than 10 projects of Provincial Natural Science Foundation and Technology Founds. Since 1993, Prof. Yu has gotten 5 awards from Guangdong Provincial Medical Health Science and Technology Progress, 4 awards from Guangdong Government of Science and Technology Prize, and 9 patents of National Invention. So far, a total of more than 30 graduated, doctoral and postdoctoral students were trained under his guides.
Yongzhan Nie, Ph.D.
The Fourth Military Medical University, China
Dr. Yongzhan Nie is currently a Professor of Molecular and Metabolic Cell Biology and vice director of both the State Key Laboratory of Cancer Biology and Department of Gastroenterology Xijing Hospital, the Fourth Military Medical University. Dr. Nie received his Ph.D. in internal medicine from the Fourth Military and Medical University and post-doctoral training at Yale University School of Medicine. Dr. Nie’s expertise includes metabolic and molecular mechanisms of fatty liver associated diseases and gastrointestinal cancers. He was awarded Changjiang Scholarship award from Minister of Education in 2010 and received the National Science Fund for Distinguished Young Scholars in 2012. Dr. Nie has published over 50 peer-reviewed manuscripts in many top ranked scientific journals, including Nature Cell Biology, Hepatology, Journal of Hepatology, Oncogene, Journal of Biochemistry etc.
Temple University, USA
Dr. Xiongwen (Wen) Chen is an associate professor of Physiology and a member of the Cardiovascular Research Center at Temple University School of Medicine. He obtained his BS and MS degrees in Animal Physiology and Biochemistry from Beijing (China) Agricultural University and PhD degree in Physiology from Temple University School of Medicine (2003). After 3 years of postdoctoral training, he moved to a faculty position as an assistant professor at Temple University in 2006 and then as an associate professor in 2014. He is also an adjunct professor of the Third Military Medical University in China. He received awards from ISHR for Best Poster Award (2001), from AHA as the Final Winner of Melvin L. Marcus Young Investigator Award (2006), from HFSA for Jay N. Cohn New Investigator Award (2007). He is also recognized as one of “The Thousand Youth Plan” from Chinese government. His research is aiming to identify novel molecular and cellular mechanisms of heart disease and to develop new therapies to prevent and treat heart disease. Specifically, his research team is trying to dissect novel aspects of calcium and adrenergic signaling in the progress of heart disease in relation to cardiac hypertrophy, heart failure and arrhythmias. He has served as a member of editorial boards of Clinical Sciences, Plos One, Frontiers in Muscle Physiology, Cardiovascular Pharmacology and Burn and Trauma. As an ad hoc reviewer, he reviews manuscripts from Circulation, Circulation Research, Cardiovascular Research, PNAS, Journal of Molecular and Cellular Cardiology, etc. He has also served as a reviewer for AHA grants, Italian Department of Health grants, Chinese 973 grants and England MRC grants. He is currently the PI for an NIH R01 and a P01 Core. More information about his research and publications can be found at:
Yingjie Chen, M.D., Ph.D.
University of Minnesota, USA
Dr. Yingjie Chen is currently an Associate Professor of Medicine in Lillehei Heart Institute and Cardiovascular Division at University of Minnesota. Dr. Chen received his Ph.D. from University of Minnesota and followed by postdoctoral training at University of Minnesota Medical School. Dr. Chen’s expertise includes heart failure (HF) induced lung remodeling, ADMA/NO/cGMP signaling and translation initiation on heart failure development. His research also focuses on the roles of dendritic cells and T cells on HF-induced heart failure. Dr. Chen has published over 70 peer-reviewed manuscripts in scientific journals such as Circulation, Circulation Research and Hypertension. Dr. Chen is currently serving as principal investigator for two NIH grants. His past publication can be found at:
Yingmei Zhang, M.D., Ph.D
The Fourth Military Medical University, China
Prof. Zhang is an associate professor and attending physician of Department of Cardiology, Xijing hospital, the Fourth Military Medical University. She is also an adjunct assistant professor of Division of Pharmaceutical Science, University of Wyoming. She got both her Master’s degree and Doctors degree in the Fourth Military Medical University and used to be Assistant Research Scientist (Post-Doctoral Fellow) and INBRE Junior Fellow in University of Wyoming, USA. She has been engaged in understanding the pathogenesis and therapeutics of myocardial mitochondrial injury under metabolic syndrome. Her major scientific contributions encompass (1) revealing novel mechanism(s) behind myocardial mitochondrial injury under ER stress via dysregulation of cytosolic Ca2+ homeostasis; (2) depicting the beneficial role for endogenous myocardial proteins including mitochondrial aldehyde dehydrogenase (ALDH2) and insulin-like growth factor I (IGF-1) under metabolic syndrome. These findings have shed promises towards identification of new therapeutic targets in heart disease. Over the past five years, she has published 27 papers in first-rated journals including Circulation as the first or corresponding author. The combined impact factor reaches 174. She has served as the principal investigator for two NSFC grants and played a major role in research awards from National Institutes of Health (NIH) and American Diabetes Association. She has been serving as a guest editor for journals such as Curr Pharm Design, BBA Mol Basis Disease and Exp Diabetes Res.
Yong Liu, Ph.D.
Chinese Academy of Sciences, China
Dr. Yong Liu received his Bachelor and Master degrees in Biochemistry from Peking University in 1986 and 1989, respectively. He obtained his Ph.D. degree in 1995 in Microbiology and Molecular Genetics from Rutgers-The State University of New Jersey and UMDNJ-RWJ Medical School. After his post-doctoral training at University of California, Santa Barbara from 1995 to 2000, Dr. Liu worked as a Senior Scientist at the Immunology Section of AlleCure/Mankind Corp., a California-based biotechnology company. In 2003, Dr. Liu joined the Institute for Nutritional Sciences as a Principal Investigator. His current research focuses on elucidating the molecular mechanisms that link cellular stress pathways and metabolic disorders.
The UPR Sensor IRE1 Links Overnutrition to Energy Imbalance in Obesity
In eukaryotic cells, accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) triggers ER stress, activating the adaptive cellular unfolded protein response (UPR). IRE1 (inositol-requiring enzyme 1), an ER-localized transmembrane signal transducer, is an ancient ER stress sensor that is conserved from yeast to humans. IRE1 possesses both protein Ser/Thr kinase and endoribonuclease (RNase) activities, and initiates a key signaling branch of the UPR via non-conventional splicing regulation of XBP1 (X-box binding protein 1). IRE1 can also degrade specific subsets of mRNAs to exert its UPR actions through a mechanism called regulated IRE1-dependent decay (RIDD). Previously we have demonstrated that mammalian IRE1 can respond to changes of the metabolic states in mice. Employing tissue-specific gene-targeting strategies, we further investigated the role of IRE1 in the progression of diet-induced obesity in mice. We found that IRE1 in immune cells plays a key role in overnutrition-induced energy imbalance. Our studies suggest that IRE1 not only functions as a regulatory switch in metabolic control, but also links nutritional stress to the pathogenesis of obesity and metabolic disorders.
Yichun Zhu, Ph.D.
Fudan University, China
Professor Yi-Chun Zhu finished his medical training in Shanghai Second Medical College (1981-1987), and specialized as a pharmacologist in University of Heidelberg in Germany (1992-1994). He started his teaching and research career on medical physiology and was appointed as lecturer and Associate Professor of physiology in Shanghai Medical University (Fudan University Shanghai Medical College since 2000) from 1995 to 1999. Since 1999, he had been appointed as a full professor of physiology (1999), director of Shanghai Key Laboratory of Bioactive Small Molecules (2014- ), Subject Chief Scientist in Physiology National key disciplines (2005- ), then associate Editor of Life Sciences (2006- ). In 2009, Prof. Zhu was elected as a member of Chang Jiang Scholars Program. In 2013, He was elected as a member of Millions of Talents Project national, and was awarded the "Young Experts with Outstanding Contributions" honorary title. He has been engaged since 1993 in the research of pathogenesis and new therapeutic method of cardiovascular disease, including that the mechanism and intervention of apoptosis in cardiac myocytes; The mechanism of cardiac ion channal regulation by hydrogen sulfide; New approach to regulate angiogenesis in ischemic hearts; Function of effective ingredient from natural products on cardiovascular system. His research activities have been supported by the National Natural Science Foundation of China (NNSFC), National Science Fund for Distinguished Young Scholars, and the National Basic Research Program of China (973 Program). He has published more than 100 scientific papers in peer-reviewed journals.
Yawei Xu, M.D, FACC
Tongji University, China
Professor Yawei Xu, M.D., doctoral mentor, Fellow of American College of Cardiology (FACC), Chief Physician, director of general medical and cardiology. At the same time, he acts as Vice-chairman of Gerontological Society of China of Cardiology, Standing Committee of Cardiology Branch of the Chinese Medical Association and of the Chinese Heart Rhythm Society, Vice Chairman of China Association of Cardiovascular Aged Care Professional Committee, Vice Chairman of Gerontological Society of China Professional Committee of cardio-cerebral vascular diseases, Vice Chairman of China Professional Committee of EECP and so on. He Specializes in diagnosis and treatment of coronary heart disease and arrhythmia intervention. He has published over 100 papers. The accumulated index factor is more than 200 in recent 3 years. He has edited four monographs as the chief editor, and over ten as the editor. He has held various large international multi-center clinical trails as a principal investigator like VIS PMS, TOTAL, VIVE, etc. He has committed to nearly 20 research topics including the National Natural Science Foundation and has got four scientific research achievements.
Xiaoli Tian, Ph.D.
Peking University, China
Xiao-Li Tian, Ph.D. Professor and Principal Investigator of Human Population Genetics, IMM (Institute of Molecular Medicine), Peking University, received his Ph.D. from Free University of Berlin, Berlin, Germany and trained as post-doctorate in Cleveland Clinic Foundation, where he identified a novel angiogenic factor AGGF1 by genetic approaches and became Staff Research Associate. In year 2006, he started to set up lab for human population genetics, searching for genetic components critical for cardiovascular aging process and related diseases by population-based genetic study and engineered animal models. Non-lipid associated atherosclerosis is one of the focus as well. At Peking University, he built the Multi-Centered Biobank of PKU (MCBP), recruiting about 170K blood samples from 5 large centers consisting of more than 17 qualified hospitals. He has two large cohorts of natural population localized in Middle West and southeast of China, consisting of 200k and 500k participants, respectively. Additionally, he also has more than 4000 centenarians in MCBP. The GWAS on coronary artery diseases has been completed and the functional characterization is undergoing. He recently became Chief Scientist of National Basic Research Program on “Molecular Basis of vascular aging and age-related cardiovascular diseases”.
Hong Yu, Ph.D.
The 2nd Affiliated Hospital of Zhejiang University, China
Dr. Yu received his BS from Fudan University in Shanghai, and PhD from University of Southern California in Los Angeles, USA. He continued his postdoctoral training for gene therapy in Dr. French Anderson’s lab at USC. He has worked in the field of cardiovascular biology for nearly 20 years. He was an associate professor at University of Miami before he was selected into the Thousand Telents Plan in Zhejiang Province and came back to China in 2011 as a Qiushi Outstanding Professor in Zhejiang University, Hangzhou. He is a Fellow of AHA (FAHA).
Dr Yu has published more than 50 peer reviewed papers. His research is focused on progenitor cell homing to ischemic tissue for angiogenesis and the effect of aging on the activity of stem cells. He has pinpointed the mechanism behind the weakened angiogenesis in the ischemic hindlimb of old mice, and linked impairments of angiogenesis in aged mice with lower CXCR4 expression in progenitor cells. His current work has been focused on how to improve the activities of stem cells for better efficacy of cell therapy for cardiovascular diseases.
Xiang Chen, M.D., Ph.D.
Huazhong University of Science and Technology,China
Xiang Cheng received his M.D. and Ph.D. degrees from Tongji Medical College of Huazhong University of Science and Technology. From February 1, 2010 to April 1, 2011, he studied in Peter Libby’s Lab at BWH, Harvard University as a visiting scholar.
Xiang Cheng is working as a professor and chief physician in the Department of Cardiology, Union Hospital. He is also the vice director of the Department of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology. Since 2008, Xiang Cheng has been the secretary of the Key Laboratory of Education Ministry for Biological Targeted Therapy, at Huazhong University of Science and Technology.
Xiang Cheng has focused his research on the role of inflammation especially T cells in cardiovascular diseases including chronic heart failure and coronary artery diseases. He has published more than 50 peer-reviewed research articles.
Xiang Wei, M.D., Ph.D.
Huazhong University of Science and Technology, China
Professor and director of the cardiovascular surgery department in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
Dr. Xiang Wei got his M.D. degree in 1997 in Tongji medical university. Then he worked as a cardiothoracic surgeon in Tongji Hospital. In 2001 and 2002~2003, he worked as a visiting scholar in Prince of Wales Hospital in Hong Kong and the University of Chiete in Italy, respectively. In 2008, he received his Ph.D. degree in Tongji Medical College, Huazhong University of Science and Technology. As a cardiovascular surgeon, he is an expert in various kinds of cardiovascular diseases, especially in coronary heart diseases and great vessel diseases. He also performed nearly 50 heart transplantations.
His main research interest focused on heart hypertrophy, heart failure and heart and lung transplantation. In 2004, as the principal investigator, “The research about when to choose thymusectomy to treat patients with myasthenia gravis (MG)” won the third prize of Science and technology progress award in Hubei province, second prize of Science and technology progress award in Wuhan city.” He has published about 30 research articles in peer-reviewed journals, including Cardiovascular Research and The Annals of thoracic surgery and so on. He was also in charge of seven grants from the NFSC, Natural science foundation of Hubei province and Wuhan city and Huazhong University of Science and Technology.
Xuehai Zhu, M.D., Ph.D.
Huazhong University of Science and Technology, China
Dr. Xuehai Zhu received his M.D. degree in 1997 in Tongji medical university. In 2000, he obtained his Ph.D. degree major in organ transplantation in Tongji Hospital. Thereafter, he worked as an attending doctor in the department of organ transplantation in Tongji hospital. From 2004~2006, he worked as a visiting scholar in University of Pittsburgh School of Medicine and in EPR center in Ohio State University College of Medicine. During this period of time, his main research interest was focused on coronary heart diseases and cardiac ischemic- reperfusion-injury. Since 2006, he worked in the cardiovascular surgery department as a surgeon and specialized in ischemic heart diseases and heart transplantation. As a scientist, he is engaged in the cellular and molecular mechanisms underlying oxidative stress of myocardium and the immunological rejection mechanisms in heart and lung transplantation. He received several grants from the NFSC as the principle investigator and published his research article in Antioxid Redox Signal, J Immunol, Am J Physiol Heart Circ Physiol and Transplant Proc etc.
Yuhua Liao, M.D., Ph.D.
Huazhong University of Science and Technology, China
Professor Yu-Hua Liao M.D., chief physician, Ph.D. candidate supervisor, director of institute of cardiology and director of cardiology department of Union Hospital in Tongji Medical College of Huazhong University of Science and Technology, Wuhan China, chief editor of Journal of clinical cardiology, leader of National Key Discipline and National Clinical Key Special Department of Cardiology, chairman of Wuhan Cardiovascular society. Pro. Liao has received special government allowance from the State Council in 1996, and was awarded the honor young expert with outstanding contributions from the Ministry of Health in 2004. His specialties are Cardiovascular Immunology and Cardiovascular Genetics. Pro. Liao is a member of AHA and Editorial Board of European Journal of Heart failure. He has published over 300 papers, 115 of which were included by science citation index (SCI) such as the journals of Nature Genetics、JACC、Cardiovas Res、Hypertension、FASEB J、JI, and edited the Cardiology and Cardiovascular Immunology as the chief editor. Pro. Liao has been successively awarded 6 prizes at national, ministerial and provincial levels, which included a second-class National Scientific and Technological Progress Award, and invented ATR12181 and ATRQβ-001 hypertensive vaccine. Pro. Liao is currently serving as principal investigator for several NSFC grants、“863” Program and National Key Technology R&D Program. Pro. Liao also is a famous expert in diagnosis and therapy of complex and difficult cardiovascular diseases.
Xiao-Dong Zhang, Ph.D.
Wuhan University, China
Xiao-Dong Zhang received his Ph.D. in Molecular Biology from School of Basic Medicine of Peking Union Medical College (PUMC) in 2000 for work on cloning and functional study of differentially expressed genes in spermatogenesis of rat and human and continued to work at PUMC. In 2004, he was a postdoctoral fellow in Georgetown University, where he was focus on the functional study of differentially expressed genes in spermatogonia using knockout mice. In 2005, he moved to Case Western Reserve University and involved in the study of dissecting the signaling pathways controlled by phosphatases that are mutated in cancer using somatic cell knockout technique. Dr. Zhang joined College of Life Sciencese in Wuhan University in August, 2008. Currently, Dr. Zhang has set up a laboratory in the Wuhan University and focuses on developing gene targeting technique and dissecting the role of NLK in myocardial angiogenesis and ischemic heart disease using genetic animal models.
Yan Zhou, M.D.,Ph.D.
Wuhan University, China
Dr. Zhou obtained Bachelor of Medicine in Tongji Medical College in 1997. He earned M.D. and Ph.D. degrees in Peking Union Medical College in 2000 and 2002 respectively. Dr. Zhou did his postdoctoral training in Dr. Weimin Zhong’s lab in the Department of Molecular, Cellular and Developmental Biology at Yale University, studying asymmetric cell divisions of neural progenitor cells (NPCs) in cortical development. His studies revealed a novel cellular mechanism that uses Golgi fragmentation and reconstitution, through changes in the subcellular distribution of an essential Numb partner, the Acbd3 protein, to coordinate cell-cycle progression and cell-fate specification during an asymmetric cell division, which is published in Cell and highlighted in Faculty of 1000 and Science Signaling. Dr. Zhou established his own research group in College of Life Sciences, Wuhan University in 2011 and studies molecular and cellular mechanisms underlying cell-fate specification in cortical development of cerebrum and gliomagenesis. His lab recently found long non-coding RNAs are key players in cell-fate determination during cortical neurogenesis. Dr. Zhou is the member of SFN, HUGO and SDB.
Zan Huang, Ph.D.
Wuhan University, China
Dr Huang got his Ph.D. from Loyola University Chicago in 2006. He received his postdoctoral training in the field of hematology and oncology at University of Chicago and Northwestern University. He was appointed as a professor in Wuhan University College of Life Sciences in 2010. Dr. Huang has longstanding research interest in understanding the mechanism and regulation of normal or malignant blood cell differentiation. Particularly, he studied interferon-signaling and transcriptional regulation in megakaryocyte differentiation (J Clin Invest, 2007; Mol Cell Biol, 2009), and TPO/c-MPL signaling in myeloproliferative neoplasms (Lekemia, 2013). Recently, his research extended to unveil the unknown function of novel genes identified in human embryo development (J Biol Chem, 2012; Cell Mol Life Sci, 2013).
He Huang, M.D., Ph.D.
Wuhan University, China
Dr. He Huang is currently a Professor of Wuhan University and he is also the deputy director of Cardiology Department in the Renmin Hospital of Wuhan University. He led 3 Projects of National Natural Science Foundation, 1 Project of the ministry of education in start-up fund, 2 Projects of Hubei Province Natural Science Fund, 1 Project of Hubei Province Science and Technology Support Program; Thus Dr. Huang involved a number of national and provincial projects. Under the tutelage of the world's leading electrophysiology expert Professor K-H Kuck during study in Germany, he participates in a variety of radiofrequency ablation of arrhythmias. He is repeatedly invited to report his results in international and domestic conferences. By now, Dr. Huang has published over 50 articles in major journals both domestically and abroad, and 4 works of academic monograph. Dr. Huang was awarded with the “New Century Excellent Talents Scheme” in 2008, the 11th "Hubei Provincial Youth Science and Technology Award" in 2013, 1 Second Prize of National Science and Technology Progress Award, 1 Second Prize of ministerial Science and Technology Progress Award, 1 First Prize of China Medical Technology, 2 First Prize of Hubei Province Science and Technology progress Award, 1 Third Prize. The main research directions: cardiac electrophysiology and interventional cardiology foundation for basic research and clinical practice. He currently serves deputy director of the 9th Youth Committee of Chinese Medical Society for cardiovascular disease; Vice chairman of the 6th Youth Committee of Chinese Medical Society of Electrophysiology and Pacing; The mentor of ministry of health of the cardiovascular disease in clinical training base; A member of the European Society of Cardiology; The council member of European Heart Rhythm Association; Wuhan University LuoJiaShan young scholars.
Bo Yang, Ph.D.
Wuhan University, China
Dr. Bo Yang is currently a Professor of Cardiology Department in Wuhan University and the deputy director of the Cardiology Department in Renmin hospital of Wuhan University, Dr. Yang has received his Ph.D. in cardiology from Wuhan University in 1998. He is the committee member of the pacemaker and electrophysiology branch of Chinese medical association, committee member and secretary of cardiovascular disease society of Hubei. Dr. Yang’s expertise includes the prevention and treatment of Coronary heart disease, various arrhythmias diseases. For his outstanding achievements, Dr.Yang was awarded several Prizes for Science and Technology Progress (STP) , including one Second Class Prize for STP of China, three First Class Prize and one Second Class Prize for STP of Hubei ,one Second Class Prize for STP of state Education Ministry ,one First Class Prize for Science and Technology Promotion of Hubei, one First Class Prize and one Second Class Prize for STP of Wuhan. In addition, Dr.Yang has edited five academic monographs and has published more than 60 papers, some of which have been in the SCI database. Dr.Yang has engaged in clinical, research and teaching work of cardiovascular disease for long time, and he has gone to United States and Italy for researching and learning cardiovascular disease. Dr.Yang is very good at doing cardiac interventional surgery, includes coronary angiography, percutaneous coronary balloon angioplasty, percutaneous coronary stent implantation, radiofrequency ablation, pacemaker implantation, ICD implantation and so on.
Hao Xia, M.D., Ph.D.
Wuhan University, China
Dr. Hao Xia is currently the vice director of Cardiology ward III, Renmin Hospital of Wuhan University. He is the member of Wuhan Branch of Cardiovascular Diseases Society of China, Youth Science and Technology Association of Hubei Province, Medical Association Expert Database of Technical Appraisal for Medical Accidents of Hubei Province, and Professional Committee of Cardiovascular and Cerebrovascular Disease of Integrative Medicine Association of Hubei Province. Dr. Xia received his Ph.D. and M.D. training in internal medicine in Wuhan University. His expertise includes coronary heart disease, hypertension and heart failure, especially in the treatment of acute myocardial infarction and other acute critically ill, interventional diagnosis and treatment of coronary heart disease and implantation of artificial cardiac pacemaker. He currently serves as the editorial member of Journal of Clinical Internal Medicine. Dr. Xia has published over 70 peer-reviewed manuscripts in many top ranked scientific journals, including Europace, Basic Research in Cardiology and hypertension. Dr. Xia is currently serving as principal investigator for several grants including National Natural Science foundation of China.
Xuejun Jiang, M.D., Ph.D
Wuhan University, China
Dr. Xuejun Jiang is currently a cardiologist, professor in the Division of Cardiovascular Diseases, Cardiology Department of the Renmin Hospital of Wuhan University. He is the member of Chinese Society of Cardiology. He is also a specialist of Hubei Provincial Interventional Cardiology quality control committee and the secretary of Hubei Provincial society of clinical investigation. Dr. Jiang received his Ph.D. and M.D. degree from TongJi Medical University and received postdoctoral training at Penseyvenia state University, Boston, MA. His main interests are the interventional cardiology and biomaterials applications. He has published about 100 international papers in recent years. He received science and technology progress awards of Hubei Province and Wuhan City in 2004, natural science award of Hubei Province in 2005. He currently serves as the reviewer of biomaterials, Annals of Biomedical Engineering, ActaBiomaterialia, International Journal of Cardiology.
Mingwei Bao, M.D.
Wuhan University, China
Vice Professor, Chief Physician
Department of Cardiology,
Youth Commissioner in Chinese Society of Pacing and Electrophysiology and Chinese ECG Information Society
Member of the Heart Electrical Group of Chinese Society of Pacing and Electrophysiology
The Invited Reviewer of Chinese Journal of Cardiac Pacing and Electrophysiology
Jiahong Xia, Ph.D.
The Central Hospital of Wuhan, China
Dr. Jiahong Xia is currently a Professor of Department of Cardiovascular Surgery, Union Hospital. He is a committee member of Chinese Society for Thoracic and Cardiovascular Surgery, the Vice Chairman of the Youth Committee of Chinese Society for Thoracic and Cardiovascular Surgery, a member and the secretary general of Society of Hubei Province for Thoracic and Cardiovascular Surgery. He completed post-doctoral training at The Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine. Dr. Xia’s expertise includes Cardiac Transplantation and Transplantation Immunology, Aortic Aneurysm, Atrial Fibrillation, particular interests in development of novel gene discovery as novel therapeutic targets for human cardiovascular diseases. Dr. Xia was awarded in 2009 the new century talents from the Ministry of education, China. In 2013, he received a Science and Technology Progress Award from the Ministry of education, China.
He currently serves in the editorial board of Chinese experimental surgery, Journal of Huazhong University of Science and Technology (English version), Journal of clinical cardiovascular disease, and Journal of clinical emergency, Dr. Xia has published over 30 peer-reviewed manuscripts in many top ranked scientific journals, including Journal of Clinical Investigation, Transplantation and Heart Lung Transplant. He has presided over a preliminary research on "973" special of the Ministry of science and technology (2010CB535012), the key project of the National Natural Science Fund (81130056), and won consecutive fund from the National Natural Science Fund, the Doctoral Fund of Ministry of education and the Hubei Province Natural Science fund.
Pengcheng Luo, M.D., Ph.D.
Huangshi Central Hospital, China
Dr. Pengcheng Luo is currently a Professor of Urology in Huangshi Central Hospital, Hubei Polytechnic University. He is the vice president of Huangshi Central Hospital, the executive vice president of Clinical School of Hubei Polytechnic University and also the director of Hubei Key Laboratory of Kidney Disease Pathogenesis and Prevention. Dr. Luo received his Ph.D. training in the Physiology Department of Medical College of Georgia and the post-doctoral training at Clinical Pharmacology Department of Vanderbilt University. His clinical interests include kidney diseases and diabetes and the research focuses on the impacts of the Eicosanoids and RAAS on the related diseases. He was awarded “Chutian Scholar” in 2013 and elected in “Hundred Talent Plan” of Hubei Province in 2014. He serves as the PhD Candidate Supervisor of Wuhan University and has published over 20 peer-reviewed manuscripts, such as in Journal of Hepatology, Diabetologia and Kidney International. Dr. Luo’s projects are currently supported by several grants including the National Nature Science Foundations of China and the Distinguished Young Scholar Foundation of Hubei Province.
Hunan Agricultural University, China
Dr. Aibing Wang is currently a Professor of Preventive Veterinary Medicine in the college of Veterinary Medicine, Hunan Agricultural University. Dr. Wang received his Ph.D. in biochemistry and molecular biology from Peking Union Medical College, Beijing, China and post-doctoral training at National Institutes of Health (NIH). He has been playing an active role in performing broad investigations ranging from the gene functions to pathological conditions, with particular emphasis on the cellular, developmental and disease-causing roles of myosin II, as well as the mechanisms underlying the development of cardiovascular and metabolic diseases. Dr. Wang has published 20 peer-reviewed manuscripts in multiple scientific journals, including PNAS, JBC, Circulation, Hypertension, and Circulation Research. Dr Wang also received several NIH Awards and served as a reviewer for several journals, such as Laboratory Investigation, International Journal Biologic Sciences, Journal of Cellular Biochemistry, Molecular and Cellular Biochemistry.
Dr. Wang was awarded Shennong Scholar from Hunan Agricultural University and set up his own lab in 2013, with the focuses on the generation of genetically modified animals and the production of vaccines against the infectious diseases in livestock.
Xianghui Fu, Ph.D.
Sichuan University, China
Dr. Xianghui Fu is currently a Professor of National Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. Dr. Fu received his Ph.D. in Biochemistry and Molecular Biology from Peking Union Medical College and post-doctoral training at University of Bergen, Norway and City of Hope National Medical Center, USA. Dr. Fu established his research group at Sichuan University in July, 2014. Dr. Fu’s research focuses on epigenetic mechanisms of cancer and metabolic diseases with particular interest in developing novel therapeutic treatments for those diseases. Dr. Fu has published over 20 peer-reviewed manuscripts in premier international journals, including PNAS, Hepatology, Mol Biol Evol and Oncogene.
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