Grant: Project Grant

Heart failure (HF) is a major cause of mortality, morbidity and healthcare costs. In Canada alone, it is estimated that 600,000 people suffered HF in 2015. Existing medications to treat HF are insufficient and prevalence is increasing. In this context, Apelin is amongst the most potent known positive inotropic compounds (i.e. enhancer of cardiac output). Using an interdisciplinary approach combining chemistry, biology, medicine and informatics, the goal of the proposed research is to validate the APJ receptor (APJr), target of the Apelin and Elabela (ELA) peptides, as a new target for the treatment of HF. Our group recently published 6 manuscripts on the cardiovascular effects of the Apelin/ELA/APJr system and the development of new analogs with improved functions. As a first objective, we will optimize stable molecules capable of strongly activating the APJr. As a second objective, we will analyze how these compounds impact cellular response, and particularly how they can selectively discriminate desired from undesired effects. We will then analyze how this cellular response translates into beneficial outcomes in cariac cells, on isolated hearts and in animals. Finally, our third objective will be to assess the impact of these new compounds on experimental models of chronic and acute heart failure, in anticipation of subsequent clinical applications. Our group of researchers is the only one in Canada and among few worldwide to possess such complementary expertises on Apelin, including E. Marsault (PhD, medicinal chemistry), P. Lavigne (structural biology), M. Auger-Messier (PhD, cardiac pathophysiology and pharmacology), P. Sarret (PhD, G Protein-Coupled Receptor pharmacology and physiology), R. Dumaine (PhD, cardiac electrophysiology), O. Lesur (MD PhD, intensive care), S. Lepage (MD, cardiology). The outcomes of the proposed research will be a validation of the potential of the Apelin/ELA/APJr and new avenues for the treatment of HF.