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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 endo-/- ) and myocardium (APJ myo-/- ). No baseline difference was observed in left ventricular function in APJ endo-/- , APJ myo-/- , or control (APJ endo+/+ , APJ myo+/+ ) mice. After exposure to transaortic constriction, APJ endo-/- mice displayed decreased left ventricular systolic function and increased wall thickness, whereas APJ myo-/- 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 2+ transients did not change with stretch in either APJ -/- or APJ +/+ cardiomyocytes. Application of apelin to APJ +/+ cardiomyocytes resulted in decreased Ca 2+ transients. Furthermore, hearts of mice treated with apelin exhibited decreased phosphorylation in cardiac troponin I NH 2 -terminal residues (Ser 22 and Ser 23 ) consistent with increased Ca 2+ 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 2+ transients while maintaining contractility through myofilament Ca 2+ 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 2+ sensitization, and identifying potential mitigating effects of apelin in APJ stretch-induced hypertrophic signaling.

The myocardium has an intrinsic ability to sense and respond to mechanical load in order to adapt to physiological demands. Primary examples are the augmentation of myocardial contractility in response to increased ventricular filling caused by either increased venous return (Frank–Starling law) or aortic resistance to ejection (the Anrep effect). Sustained mechanical overload, however, can induce pathological hypertrophy and dysfunction, resulting in heart failure and arrhythmias. It has been proposed that angiotensin II type 1 receptor (AT1R) and apelin receptor (APJ) are primary upstream actors in this acute myocardial autoregulation as well as the chronic maladaptive signaling program. These receptors are thought to have mechanosensing capacity through activation of intracellular signaling via G proteins and/or the multifunctional transducer protein, β-arrestin. Importantly, ligand and mechanical stimuli can selectively activate different downstream signaling pathways to promote inotropic, cardioprotective or cardiotoxic signaling. Studies to understand how AT1R and APJ integrate ligand and mechanical stimuli to bias downstream signaling are an important and novel area for the discovery of new therapeutics for heart failure. In this review, we provide an up-to-date understanding of AT1R and APJ signaling pathways activated by ligand versus mechanical stimuli, and their effects on inotropy and adaptive/maladaptive hypertrophy. We also discuss the possibility of targeting these signaling pathways for the development of novel heart failure therapeutics. [ABSTRACT FROM AUTHOR]