APJ acts as a dual receptor in cardiac hypertrophy

APJ is shown to be a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin, a finding that is important for the development of APJ agonists to treat heart failure. Apelin receptor's dual role in heart disease G-protein-coupled receptors (GPCRs) have been widely implicated in the control of cardiac function. Here, a GPCR known as APJ is shown to be a bifunctional receptor involved in the conversion from increased contractility of the heart to cardiac failure. In response to its ligand apelin, which is known to be cardioprotective, APJ mediates adaptive remodelling. Conversely, stretch-dependent apelin-independent APJ activation accounts for pathological remodelling. These findings are important for the development of APJ agonists as treatments for heart failure. Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues 1 . Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gα i and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gα i . Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.