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

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.

Role of the Vasopressin/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in Water Metabolism Disorders

“…Finally, intravenous injection of K17F in increasing doses in lactating rats increases diuresis in a dose-dependent manner concomitantly with a significant decrease in urine osmolality and a decrease in AQP2 insertion at the apical membrane of CD (77), showing that K17F-induced diuresis is linked to a direct action of apelin on CD. Similarly, in other studies (78, 79), acute or chronic intravenous treatment with apelin-13 potently increased diuresis in male Sprague-Dawley rats.…”

Apelins, ELABELA, and their derivatives: Peptidic regulators of the cardiovascular system and beyond

“…In physiological conditions, both ligands exert powerful cardiac and vasoactive actions . Indeed, infusion of apelin‐13 increases cardiac contractility while decreasing cardiac loading (positive inotropic effect), dilates blood vessels without compromising their permeability, and promotes blood vessel sprouting . Similar results were observed with ELA .…”

“…Indeed, infusion of apelin‐13 increases cardiac contractility while decreasing cardiac loading (positive inotropic effect), dilates blood vessels without compromising their permeability, and promotes blood vessel sprouting . Similar results were observed with ELA . While the apelinergic system is abundantly expressed in endothelial cells to regulate the properties of the vascular system, recent findings highlighting its significant expression in platelets suggest it might exert antithrombotic actions that require further study .…”

“…Murza et al reported the identification of a shorter bioactive fragment, ELA(19–32), which corresponds to the 14 C ‐terminal amino acids of native ELA (Figure ). ELA(19–32) was shown to bind the apelin receptor with sub‐nM affinity, and to activate the Gα i1 and β‐arrestin2 signaling pathways with potencies close to that of full‐size ELA . When administered to rats, this shorter analogue induced a drop in MABP and a LVDP effect of lower magnitude compared to that of apelin‐13 and ELA.…”

Development and validation of an LC-MS/MS method for detection and quantification of in vivo derived metabolites of [Pyr1]apelin-13 in humans

“…Previous studies investigating the metabolism of apelin peptides were largely conducted in plasma in vitro or in rodent models neither of which may represent metabolism in humans. These studies demonstrated that apelin peptides are very labile in plasma with a half-life of less than 1-5 minutes in vitro [20][21][22][23][24] . This plasma instability has to date been attributed the enzymatic activity of neprilysin 25 and angiotensin converting enzyme II (ACE2) [22][23][24] , and more recently plasma kallikrein 26,27 .…”