Abstract 1475: The Apelin-APJ Pathway Is an Endogenous Regulator of Cardiac Function and Is Upregulated in Cardiac Pressure Overload
The inotropic and vasoactive properties of the ligand apelin and its cognate G-protein coupled receptor APJ have been characterized by administration of exogenous peptide, but the function of endogenous apelin on the cardiovascular system is not well described. To investigate the tonic effects of apelin-APJ in contractile function, we generated and characterized apelin and APJ null mice. We also investigated the regulation of apelin and APJ receptor expression in response to cardiac pressure overload. While knockout apelin mice were viable and fertile, APJ null mice showed evidence of fetal wastage for approximately half of the embryos. Compared to wild-type controls, APJ deficient mice reaching adulthood had significantly reduced exercise capacity (treadmill runtime: 20.30 ± 0.974 vs. 23.64 ± 0.737, P=0.009) and LV fractional shortening by echocardiography (29.88 ± 0.927% vs. 44.93 ± 2.66%, P<0.0001). Isolated myocytes from APJ knockouts exhibited reduced sarcomeric shortening (5.070 ± 0.413% vs. 6.978 ± 0.405%, P=0.002) as well as velocity of contraction and relaxation, with no difference in calcium transients. These findings were recapitulated in apelin null mice. Compared to littermate controls, apelin null mice manifested modest decreases in exercise capacity, left ventricular ejection fraction, and end-systolic elastance. Isolated myocytes lacking apelin exhibited reduced sarcomeric shortening despite similar calcium transients. To investigate alterations in the apelin-APJ pathway with cardiac stress, we employed two models of pressure overload: transverse aortic constriction and pulmonary artery banding. Levels of apelin and APJ mRNA were significantly elevated in the left atria and left ventricles of TAC mice compared to sham controls. Correspondingly, levels of apelin and APJ were also significantly increased in the right atria and right ventricles of mice subjected to pulmonary artery banding. These experiments reveal a critical role for the apelin-APJ pathway in tonic myocardial function. Furthermore, we observe upregulation of both apelin and APJ receptor mRNA levels in response to cardiac pressure overload. Together, these data suggest that apelin has a functional role in both basal and compensated cardiac function.