Abstract 453: Apelin Regulates Cardiac Contractility and Rescues Neurohormonal Heart Failure
Targets of acute heart failure (HF) therapy include vascular resistance, contractility, the renin-angiotensin system, and arginine vasopressin. We have reported a role for the G protein coupled apelin-APJ receptor axis in human HF and have shown exogenous apelin-mediated changes in vascular resistance and ventricular elastance in mice. To investigate the effect of endogenous apelin, we generated an apelin knockout (KO) mouse by homologous recombination. We found apelin KO mice have lower exercise capacity, resting and maximal oxygen consumption, ejection fraction(EF), and left ventricular (LV) elastance than wild type (WT) controls. To determine a mechanism, we examined isolated ventricular myocytes, and found KO cells had decreased sarcomere shortening, suggesting an autocrine effect of apelin signaling on contractility. Intracellular calcium concentration was similar in the groups, suggesting the inotropic effect of apelin is mediated by altered tonic myofilament calcium sensitivity. Phosphorylation of myofilament protein troponin I at serine 23–24, assessed by immunoblotting, was also similar in KO and WT hearts, suggesting a difference in intracellular alkalinization as the mechanism for altered myofilament sensitivity in the KO. We next examined loss of apelin-APJ signaling in HF, with a neurohormonal HF model induced by infusion of angiotensin II and isoproterenol(n=10 per group) in KO and WT mice. No difference in echo assessed HF severity was seen between groups, consistent with prior reported downregulation of apelin and APJ in severe HF. When apelin was concomitantly infused in a third group of WT mice (n=10), severe HF was completely abrogated and normal contractility maintained. A doubling of vasopressin was found only in the apelin KO group in HF as well. Thus, apelin-APJ signaling inhibits vasopressin release, has a novel autocrine effect on sarcomeric function likely mediated by altered calcium sensitization, and demonstrates rescue of a neurohormonal HF model. These data, in combination with previous data suggesting apelin reduces vascular resistance, increases LV elastance and contractility, and likely counter-regulates renin-angiotensin, suggests this pathway is uniquely attractive as a therapeutic target in acute HF.