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Discovery and Structure–Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions

2016; American Chemical Society; Volume: 59; Issue: 7 Linguagem: Inglês

10.1021/acs.jmedchem.5b01549

1520-4804

Alexandre Murza, Xavier Sainsily, David Coquerel, Jérôme Côté, Patricia Marx, Élie Besserer‐Offroy, Jean‐Michel Longpré, Jean Lainé, Bruno Reversade, Dany Salvail, Richard Leduc, Robert Dumaine, Olivier Lesur, Mannix Auger‐Messier, Philippe Sarret, Éric Marsault,

Cardiovascular, Neuropeptides, and Oxidative Stress Research

ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELA's structure–activity relationships and report the identification of analogue 3 (ELA(19–32)), a fragment of ELA that binds to APJ, activates the Gαi1 and β-arrestin-2 signaling pathways, and induces receptor internalization similarly to its parent endogenous peptide. An alanine scan performed on 3 revealed that the C-terminal residues are critical for binding to APJ and signaling. Finally, using isolated-perfused hearts and in vivo hemodynamic and echocardiographic measurements, we demonstrate that ELA and 3 both reduce arterial pressure and exert positive inotropic effects on the heart. Altogether, these results present ELA and 3 as potential therapeutic options in managing cardiovascular diseases.