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Biology and Pharmacology of Cardio-Vascular Remodeling

Principal investigator :
Jean-Sébastien Hulot, MD PhD, Professor

Research team :

Florent Soubrier, Anne-Marie Lompré, Sophie Nadaud, Catherine Pavoine, Richard Isnard, Pascal Leprince, Claude Le Feuvre, Christian Funck-Brentano

Heart failure (HF) is a major health problem in Western countries. The prevalence of symptomatic heart failure is estimated as between 0.4% and 2.0% of the general population in Europe (Euro Heart Survey 2) and approximately 500,000 people in France have heart failure, with approximately 120,000 new cases per year. Heart Failure (HF) remains a leading cause of mortality and morbidity in Europe and its prevalence will continue to grow up in the next years with the ageing of population. Congestive HF is the final consequence of diverse cardiovascular disorders including atherosclerosis, cardiomyopathy and hypertension.
Despite progress in the standard pharmacological treatment and the benefit of device therapies in some sub-groups of patients, there is a need for innovative approaches to reverse the course of ventricular dysfunction. Our aims are to understand the molecular and cellular mechanisms involved in cardiac remodeling and to identify relevant targets to reverse the remodeling process or alternatively promote the tissue repair. The description of cellular and molecular alterations during HF has provided rationale for directly intervening within the molecular foundation of cardiomyocytes. Through an active collaboration with the Cardiovascular Research Center at Mount Sinai School of Medicine, New York (Director Pr Hajjar) the team is involved in the development of new targeted molecular therapies for heart failure. Our projects focus on deciphering the alterations in calcium cycling and signalling in cardiac myocytes and in the development of approaches to restore or silence key regulators of such defects. The projects are going from the target identification to the evaluation of new therapies in experimental animal models as well as in humans.

In line with our expertise in cardiac and vascular biology, we are also interested in understanding the molecular and cellular mechanisms involved in vascular remodeling, especially pulmonary arterial hypertension. Pulmonary artery hypertension (PAH) is a severe vascular disease characterized by chronically elevated pulmonary artery pressure. PAH can be idiopathic, hereditary or associated with other conditions including heart diseases and heart failure. The pathological mechanisms leading to this progressive and fatal cardiovascular disorder remain unknown although pulmonary-artery endothelial cell dysfunction and structural remodeling of the pulmonary vessels are early features of PAH. Pulmonary vascular remodeling includes proliferation and migration of pulmonary artery smooth muscle cells (PASMC) leading to medial hypertrophy, increased pulmonary vascular resistance and PAH progression. We have previously shown that cardiac and vascular myocytes remodeling share many common intracellular mechanisms including alterations in calcium cycling and signaling. The project aims at identifying novel genes responsible for PAH and others hereditary angiopathies, at integrating their roles in the physiopathology of the disease by experimental studies and at determining the specific role of resident vascular progenitors involved in vascular remodelling. Predisposing genes are searched for by genetic approaches in humans often requiring international collaborative studies. The functional studies are conducted using cell culture models for cell proliferation, migration, differentiation, in vivo and in vitro angiogenesis, pathological tissues from experimental models and humans, and ultimately gene disruption or gene transfer in vascular models in mice.

FOCUS

Our research programs mainly focus on two different diseases namely heart failure and pulmonary arterial hypertension. The final objective is to identify relevant targets to reverse the remodeling process or alternatively promote the tissue repair.


BIOSKETCH

Dr Jean-Sébastien Hulot is Professor of Medicine, Pharmacology at Pierre et Marie Curire Paris 6 University. He is a medical cardiologist and received his MD degree at Paris University Hospitals and his PhD degree in clinical and experimental pharmacology at the René Descartes Paris 5 University. In 2002, he joined the faculty at Pierre et Marie Curie Paris 6 University, Division of Cardiovascular Pharmacology as an Assistant Professor, and in 2006 he was promoted to Associate Professor. In 2008, he was recipient of the Leducq Foundation Transatlantic fellowship and visited the cardiovascular research  center at Mount Sinai to gain experience on the development of new therapeutic approaches to prevent the harmful structural changes to the heart in patients with heart failure. In 2010, he served as an Associated Professor of Medicine, Cardiology at the Cardiovascular Research Center at Mount Sinai School of Medicine in New York. He was appointed as the Director of Pharmacogenomics and Personalized Therapeutics.  Since 2010, he is part of the associated international laboratory « Transatlantic Cardiovascular Research Center » that was agreed between INSERM, Paris 6 University and Mount Sinai School of Medicine.

Dr. Hulot’s major research interests are in the molecular basis of cardiovascular disorders. The overall aim is the development of new predictive tools and more personalized therapeutics for cardiac diseases. He has published over 100 original articles and review articles.

He has an extensive background in clinical and basic research in cardiovascular pharmacology. He is interested in deciphering the molecular and cellular mechanisms involved in cardiovascular remodeling. A major focus of his work is elucidation mechanisms that drive defective intracellular calcium handling. He is interested in developing genome-guided therapies for cardiovascular diseases including gene therapy for heart failure patients.

 

 


Publications

1. Germain M, Eyries M, Montani D, Poirier O, Girerd B, Dorfmüller P, Coulet F, Nadaud S, Maugenre S, Guignabert C, Carpentier W, Vonk-Noordegraaf A, Lévy M, Chaouat A, Lambert JC, Bertrand M, Dupuy AM, Letenneur L, Lathrop M, Amouyel P, de Ravel TJ, Delcroix M, Austin ED, Robbins IM, Hemnes AR, Loyd JE, Berman-Rosenzweig E, Barst RJ, Chung WK, Simonneau G, Trégouët DA, Humbert M, Soubrier F.

Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension

Nature Genetics. 2013 May;45(5):518-21

 

2. Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M, Trégouët DA, Borczuk A, Rosenzweig EB, Girerd B, Montani D, Humbert M, Loyd JE, Kass RS, Chung WK.
A novel channelopathy in pulmonary arterial hypertension

New England Journal of Medicine. 2013 Jul 25;369(4):351-61

 

3. Hadri L, Kratlian RG, Benard L, Maron BA, Dorfmüller P, Ladage D, Guignabert C, Ishikawa K, Aguero J, Ibanez B, Turnbull IC, Kohlbrenner E, Liang L, Zsebo K, Humbert M, Hulot JS, Kawase Y, Hajjar RJ, Leopold JA.

Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension

Circulation. 2013 Jul 30;128(5):512-23

 

4. Yaniz-Galende E, Chen J, Chemaly E, Liang L, Hulot JS, McCollum L, Arias T, Fuster V, Zsebo KM, Hajjar RJ.
Stem cell factor gene transfer promotes cardiac repair after myocardial infarction via in situ recruitment and expansion of c-kit+ cells

Circulation Research. 2012 Nov 9;111(11):1434-45

 

5. Hulot JS, Fauconnier J, Ramanujam D, Chaanine A, Aubart F, Sassi Y, Merkle S, Cazorla O, Ouillé A, Dupuis M, Hadri L, Jeong D, Mühlstedt S, Schmitt J, Braun A, Bénard L, Saliba Y, Laggerbauer B, Nieswandt B, Lacampagne A, Hajjar RJ, Lompré AM, Engelhardt S.
Critical role for stromal interaction molecule 1 in cardiac hypertrophy

Circulation. 2011 Aug 16;124(7):796-805