Exercise training-enhanced reactive oxygen species as protective mechanisms in the coronary microcirculation

项目摘要 定期锻炼是一种被证实的、有效的、成本效益高的治疗和继发性心脏病的干预措施 预防冠心病。然而，详细了解基本的细胞和 缺乏运动诱导的心脏保护的分子机制，限制了 为疾病患者制定有效的新治疗策略。尽管最近在升值方面取得了进展 活性氧物种(ROS)作为细胞信号转导的关键调节物质，其具体贡献的细节 这些分子对血管系统中的生理信号和功能适应仍有待研究 已澄清。在冠脉微循环中尤其如此，在那里研究确定贡献 ROS在控制血流方面的作用是稀少的。拟议的研究将利用体外和体内研究的组合。 确定运动诱导的ROS信号适应如何影响血管反应性的活体方法 冠状动脉血流同时流入对照和缺血心肌，这是一个在很大程度上尚未被探索的区域 在冠脉循环中。最重要的假设是，ROS在 运动训练诱导冠脉微循环血管扩张反应的恢复 增强高危心肌的灌流和收缩功能。目标1将决定运动训练- 慢性冠状动脉闭塞心脏ROS产生的诱导适应。目标2将 确定运动训练对候选信号源的表达和亚细胞定位的影响 大鼠心脏微血管内皮细胞ROS产生及相关调节亚基蛋白 到慢性冠状动脉闭塞。目标3将确定运动训练促进的适应 ROS介导的心脏微动脉扩张的下游信号通路(S) 慢性冠状动脉闭塞。目标4将确定运动训练的信号机制 增强静息和多巴酚丁胺诱导的心肌局部血流灌注和心肌收缩功能 慢性冠脉闭塞心脏的心肌应激反应。这些研究具有很高的影响，因为 所获得的知识将为ROS在心血管系统中的保护作用提供新的见解。这个 拟议的研究将提供重要的新信息，对人类有重大的机械性洞察 并确定ROS信号在控制健康人冠状动脉血流量中的作用， 疾病和运动适应。

Project Summary Regular exercise is a proven, powerful and cost-effective intervention for the treatment and secondary prevention of coronary artery disease. However, a detailed understanding of the fundamental cellular and molecular mechanisms that underlie exercise-induced cardioprotection are lacking, limiting the development of effective new therapeutic strategies for diseased patients. Despite recent advances in the appreciation of reactive oxygen species (ROS) as critical regulators of cell signaling, the details of the specific contributions of these molecules to physiologic signaling and functional adaptions in the vascular system remain to be elucidated. This is particularly true in the coronary microcirculation where studies determining the contributions of ROS in the control of blood flow are sparse. The proposed studies will utilize a combination of in vitro and in vivo approaches to determine how exercise-induced adaptations in ROS signaling affect vascular reactivity and coronary blood flow into both control and ischemic myocardium, an area that has been largely unexplored in the coronary circulation. The overarching hypothesis is that ROS play a critical and protective role in the exercise training-induced restoration of vasodilation responses in the coronary microcirculation and thereby enhances perfusion and contractile function of the at-risk myocardium. Aim 1 will determine exercise training- induced adaptations in ROS production in hearts subjected to chronic coronary artery occlusion. Aim 2 will determine the effects of exercise training on the expression and subcellular localization of candidate sources of ROS production and associated regulatory subunit proteins in microvascular endothelium of hearts subjected to chronic coronary artery occlusion. Aim 3 will identify the adaptations by which exercise training promotes downstream signaling pathway(s) for ROS-mediated dilation in arterioles isolated from hearts subjected to chronic coronary artery occlusion. Aim 4 will identify the signaling mechanisms by which exercise training enhances regional perfusion and myocardial contractile function at rest and during dobutamine-induced myocardial stress in hearts subjected to chronic coronary occlusion. These studies are of high impact since the knowledge gained will provide novel insight into the protective role of ROS in the cardiovascular system. The proposed studies will provide important new information with significant mechanistic insight into human ischemic heart disease and identify the role of ROS signaling in the control of coronary blood flow in health, disease, and exercise adaptation.