The aim of this study is to investigate the mechanism of apelin-APJ mediated increased cardiac contractility. Apelin is an endogenous 77 amino-acid pre-pro peptide that is expressed primarily in the endothelium and is a positive inotrope that may have salutary actions in patients with heart failure. The receptor for apelin is APJ, a G-protein coupled receptor expressed on myocardial cells, endothelial cells, and smooth muscle cells. Studies have identified other putative physiologic roles for the apelin-APJ axis, including antagonism of the angiotensin pathway, central regulation of fluid balance, and adipoinsular signaling. More recently, apelin and APJ have been implicated in cardiovascular disease states. Apelin is downregulated in advanced heart failure and animals lacking the APJ receptor are hypersensitive to angiotensin II induced hypertension. Conversely, apelin infusion supports contractility and improves hemodynamic parameters in models of ischemic cardiomyopathy, and reduces blood pressure in spontaneously hypertensive rats. The protein is also downregulated in low flow conditions, and is upregulated in settings of hypoxia and oxidative stress.
We aim to study the mechanism of apelin-APJ mediated increased cardiac contractility. We will begin by characterizing the intracellular signaling following myocardial APJ activation. We hypothesize that the APJ receptor dual couples with pertussive sensitive (Gi) and pertussive insensitive (Gq/11) proteins. We further hypothesize that apelin-APJ signaling increases cardiac contractility through troponin I phosphorylation leading to enhanced myofilament calcium sensitivity. We will then perform experiments to determine whether stretch potentiates apelin-APJ induced cardiac contractility and hypertrophy. We postulate that stretch and apelin-APJ signaling act synergistically to increase the contractility of isolated cardiomyocytes. We further hypothesize that the apelin-APJ pathway exacerbates cardiac hypertrophy whereas APJ deficient mice are protected from hypertrophy. Cardiovascular disease is a leading cause of morbidity, mortality, and health care expenditure in the United States. The recently discovered apelin-APJ pathway is implicated in the development of conditions such as congestive heart failure and hypertensive heart disease. This system warrants further investigation with the aim of developing new therapies to combat human disease.
| Charo, David N; Ho, Michael; Fajardo, Giovanni et al. (2009) Endogenous regulation of cardiovascular function by apelin-APJ. Am J Physiol Heart Circ Physiol 297:H1904-13 |
