Préservation de la contractilité et de la structure des cardiomyocytes dans l'insuffisance cardiaque

 

Mannix Auger-Messier

Centre de recherche clinique Étienne-Le Bel du CHUS

 

Domaine : santé circulatoire et respiratoire

Programme chercheurs-boursiers Junior 1

Concours 2014-2015

In Canada, the highest morbidity and mortality rates amongst the adult population are due to cardiovascular diseases. The progressive drop of cardiac contractility observed with heart failure patients is ultimately fatal. It is thus crucial to better understand by which molecular mechanisms cardiomyocytes (contractile cells of the heart) preserve the cardiac output in order to develop new therapeutic strategies aimed to prevent heart diseases progression.

In order to minimize the negative impact of different stressors (e.g. arterial hypertension, myocardial infarction, cardiac valves calcification, and diabetes), the heart increases its mass and contractile force in an initial adaptive phase. A wide spectrum of proteins helps to orchestrate this hypertrophic and adaptive phase of the heart. Ironically, chronic activation of some of those same proteins also drives the progressive loss of structural and functional integrity of the heart. The mitogen-activated protein kinase p38 action on the myocardium is such an example. In fact, p38 kinase activity is essential for cardiomyocytes survival in response to stress. However, p38 kinase activity also greatly reduces cardiomyocytes contractility by an unknown mechanism and so, feeds-forward heart failure progression. Elucidating by which molecular mechanisms p38 activity is controlled in the heart might be of paramount importance for prevention of cardiomyopathies. Interestingly, few «Dual-specificity phosphatases» (DUSPs) and «ArfGAP with dual PH domains» (ADAPs)  known to counteract p38 kinase activity are indeed expressed in the heart.

Our first goal is to evaluate how important and efficient the DUSPs and ADAPs are at blocking p38 kinase detrimental action and so, at preserving structural and functional integrity of the heart. The overall objective of the proposed research program is to provide novel therapeutic avenues for heart failure treatment.