Apelin and APJ orchestrate complex tissue-specific control of cardiomyocyte hypertrophy and contractility in the hypertrophy-heart failure transition

Abstract

The G protein-coupled receptor APJ is a promising therapeutic target for heart failure. Constitutive deletion of APJ in the mouse is protective against the hypertrophy-heart failure transition via elimination of ligand-independent, β-arrestin-dependent stretch transduction. However, the cellular origin of this stretch transduction and the details of its interaction with apelin signaling remain unknown. We generated mice with conditional elimination of APJ in the endothelium (APJ) and myocardium (APJ). No baseline difference was observed in left ventricular function in APJ, APJ, or control (APJ, APJ) mice. After exposure to transaortic constriction, APJ mice displayed decreased left ventricular systolic function and increased wall thickness, whereas APJ mice were protected. At the cellular level, carbon fiber stretch of freshly isolated single cardiomyocytes demonstrated decreased contractile responses to stretch in APJ cardiomyocytes compared with APJ cardiomyocytes. Ca transients did not change with stretch in either APJ or APJ cardiomyocytes. Application of apelin to APJ cardiomyocytes resulted in decreased Ca transients. Furthermore, hearts of mice treated with apelin exhibited decreased phosphorylation in cardiac troponin I NH-terminal residues (Ser and Ser) consistent with increased Ca sensitivity. These data establish that APJ stretch transduction is mediated specifically by myocardial APJ, that APJ is necessary for stretch-induced increases in contractility, and that apelin opposes APJ's stretch-mediated hypertrophy signaling by lowering Ca transients while maintaining contractility through myofilament Ca sensitization. These findings underscore apelin's unique potential as a therapeutic agent that can simultaneously support cardiac function and protect against the hypertrophy-heart failure transition. NEW & NOTEWORTHY These data address fundamental gaps in our understanding of apelin-APJ signaling in heart failure by localizing APJ's ligand-independent stretch sensing to the myocardium, identifying a novel mechanism of apelin-APJ inotropy via myofilament Ca sensitization, and identifying potential mitigating effects of apelin in APJ stretch-induced hypertrophic signaling.

Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling

“…Recently, the tissue-specific deletion of the APJ receptor in endothelial cells or myocardial cells was reported [39]. In TAC (Transverse Aortic Constriction) pressure overload models, APJ deletion in endothelial cells increased cardiac fibrosis and decreased heart contractility, whereas the cardiomyocyte-specific deletion of APJ suppressed cardiac hypertrophy and improved heart function [40]. Therefore, the favorable effects of apelin in the heart are likely mediated through complex cellular interactions and signaling.…”

Stress-induced Differential Gene Expression in Cardiac Tissue

“…It induces cAMP synthesis, as well as activating the PI3K/Akt signaling pathway [37]. The concentration of apelin is reduced in the failing heart [40] and the contractile function is impaired in cardiomyocytes with knockout for APLNR [41]. Apelin expression was downregulated under stress when no ICI118,551 treatment was given, although the expression of its receptor (APLNR) was reduced when the β 2 -AR was blocked.…”

Stress-induced differential gene expression in cardiac tissue

“…It also induces cAMP synthesis, as well as activating the PI3K-Akt signaling pathway 33 . The concentration of apelin is reduced in the failing heart 36 and the contractile function is impaired in cardiomyocytes with knockout for APLNR 37 . Apelin expression was downregulated under stress when no ICI118,551 treatment was given, although the expression of its receptor (APLNR) was reduced when the β 2 -AR was blocked.…”