Apelin Increases Cardiac Contractility via Protein Kinase Cε- and Extracellular Signal-Regulated Kinase-Dependent Mechanisms

Abstract

BackgroundApelin, the endogenous ligand for the G protein-coupled apelin receptor, is an important regulator of the cardiovascular homoeostasis. We previously demonstrated that apelin is one of the most potent endogenous stimulators of cardiac contractility; however, its underlying signaling mechanisms remain largely elusive. In this study we characterized the contribution of protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) to the positive inotropic effect of apelin.Methods and ResultsIn isolated perfused rat hearts, apelin increased contractility in association with activation of prosurvival kinases PKC and ERK1/2. Apelin induced a transient increase in the translocation of PKCε, but not PKCα, from the cytosol to the particulate fraction, and a sustained increase in the phosphorylation of ERK1/2 in the left ventricle. Suppression of ERK1/2 activation diminished the apelin-induced increase in contractility. Although pharmacological inhibition of PKC attenuated the inotropic response to apelin, it had no effect on ERK1/2 phosphorylation. Moreover, the apelin-induced positive inotropic effect was significantly decreased by inhibition of MLCK, a kinase that increases myofilament Ca2+ sensitivity.ConclusionsApelin increases cardiac contractility through parallel and independent activation of PKCε and ERK1/2 signaling in the adult rat heart. Additionally MLCK activation represents a downstream mechanism in apelin signaling. Our data suggest that, in addition to their role in cytoprotection, modest activation of PKCε and ERK1/2 signaling improve contractile function, therefore these pathways represent attractive possible targets in the treatment of heart failure.

Cardiac action of the first G protein biased small molecule apelin agonist

“…The predominant isoform in the human cardiovascular system is [Pyr 1 ]apelin-13 [3]. Infusion of apelin leads to vasodilatation, in humans in vitro [3] and in vivo [4] and in rodents in vivo [5], as well as cardiac inotropy in vitro [3], [6], [7] and in vivo in rats [8], [9], [10], mice [11] and humans [12] without hypertrophy.…”

Effects of apelin on the cardiovascular system

“…This hypothesis found support when measurements of the sarcomere shortening in isolated cardiomyocytes showed that the positive inotropic effect was not accompanied by any increase in Ca 2+ concentration [17,85]. Recently, Perjés et al [75] demonstrated that the raises in myofilament Ca 2+ sensitivity and cross-bridge kinetics is due to the phosphorylation of regulatory myosin light chain (RMLC) via myosin light chain kinase (MLCK) (Fig. 3).…”

“…A short lasting inotropic effect was also seen in isolated adult rat cardiomyocytes, where the sarcomere shortening increased for 1 -2 min only in response to apelin-16 superfusion (1-10 nM) and returned to the control before the superfusion was discontinued [17]. The different duration of the effect does not seem to be depend on the different isoforms, because (pyr)apelin-13, apelin-13 and apelin-36 show comparable potency and efficacy in inducing positive inotropic effect [8,75]. On the other hand the importance of different procedures of contractility assessment cannot be disregarded.…”

“…Apelin is reported to potentiate myocardial inotropy in isolated preparations and intact animals [74,24,8,25,17,75,41,69]. For this reason it has been suggested as a tool for the treatment of heart failure (HF) [76,70,24,67,77,78].…”

The Emerging Potential of the Apelin-APJ System in Heart Failure

“…37 The observation that b-blockers or angiotensin II receptor antagonists (ARBs), both cornerstones of contemporary disease-modifying HF therapy, do not attenuate apelin-induced inotropy is notable should apelin supplementation go on to become a realistic therapeutic goal in HF. 37 Crucially, apelin appears to exert its inotropic effects by increasing myofilament sensitivity to calcium without exerting the potentially deleterious effects of increasing intracellular cyclic adenosine monophosphate or calcium concentrations, 38,39 both of which are thought to account for the arrhythmogenic potential of established inotropic agents. No inotrope to date has been shown to improve outcomes in acute decompensated HF.…”