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

描述(申请人提供)：本研究的目的是研究apelin-APJ信号在血管疾病中的作用。APJ是一种G蛋白偶联受体，与血管紧张素II-AI受体有31%的同源性。最近发现的APJ受体配体apelin是一种强有力的循环肌力调节剂，具有一氧化氮依赖的血管扩张特性。研究已经确定了apelin-APJ轴的其他可能的生理作用，包括对液体平衡的中枢调节，血管紧张素途径的拮抗，以及点信号。最近，apelin和apj被认为与心血管疾病有关。Apelin在晚期心力衰竭中下调，缺乏APJ受体的动物对血管紧张素诱导的高血压高度敏感。相反，在缺血性心肌病模型中，apelin输注支持收缩和改善血流动力学参数，并降低自发性高血压大鼠的血压。该蛋白在低流量条件下也下调，在低氧和氧化应激环境下上调。我们假设apelin-APJ通路也与动脉粥样硬化和血管重塑等血管疾病状态有关。Querterous实验室已经成功地创造了apelin和APJ基因敲除小鼠，这些突变正被交叉到apoE缺陷背景和其他相关的遗传模型中，以研究改变的apelin-APJ信号对疾病过程的影响。将进行动脉粥样硬化形成和血管重塑的定量分析。为了阐明apelin调节这些效应的机制，实验将包括对炎症标记物产生和内皮细胞激活的具体分析。此外，一氧化氮的作用将通过对NO产量的定量测量来质疑。最终，我们的目标是清楚地阐明APELIN-APJ系统在血管疾病中的作用，并确定发病的分子途径。心血管疾病是美国发病率、死亡率和医疗保健支出的主要原因。最近发现的apelin-APJ通路与充血性心力衰竭和高血压性心脏病等疾病的发生有关。这一系统值得进一步研究，目的是开发抗击人类疾病的新疗法。

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.