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

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

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

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.
Original languageEnglish (US)
Pages (from-to)2962-2972
Number of pages11
JournalJournal of Medicinal Chemistry
Volume59
Issue number7
DOIs
StatePublished - Apr 28 2016
Externally publishedYes

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