The role of the apelin-APJ pathway in vascular wall disease

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The aim of this study is to investigate the role of apelin-APJ signaling in vascular disease. APJ is a G protein-coupled receptor with 31% homology to the angiotensin II type-AI receptor. The recently identified APJ receptor ligand, apelin, is a potent circulating inotrope and with nitric oxide-dependent vasodilatory properties. Studies have identified other putative physiologic roles for the apelin-APJ axis, including the central regulation of fluid balance, antagonism of the angiotensin pathway, 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 ll-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 hypothesize that the apelin-APJ pathway is also involved in vascular disease states such as atherosclerosis and vascular remodeling. The Quertermous laboratory has successfully created apelin and APJ knockout mice, and these mutations are being crossed onto the apoE deficient background and other pertinent genetic models to study the impact of altered apelin-APJ signaling on disease processes. Quantitative analysis of atherogenesis and vascular remodeling will be performed. Experiments to elucidate the mechanism by which apelin modulates these effects will include specific analysis of inflammatory marker production and endothelial cell activation. Furthermore, the role of nitric oxide will be queried with quantitative measurement of NO production. Ultimately, we aim to clearly elucidate the role of the apelin-APJ system in vascular disease, and identify the molecular pathways by which pathogenesis occurs. 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.