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

项目摘要 定期锻炼是一种行之有效的，强大的和具有成本效益的治疗和辅助干预措施。 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，限制了运动的发展。 有效的新治疗策略。尽管最近的进展， 活性氧（ROS）作为细胞信号传导的关键调节剂， 这些分子在血管系统中的生理信号和功能适应仍有待进一步研究。 阐明。这在冠状动脉微循环中尤其如此，其中研究确定 在控制血液流动中的活性氧是稀疏的。拟议的研究将利用体外和体内的组合。 确定运动诱导的ROS信号适应如何影响血管反应性的体内方法 和冠状动脉血流进入对照和缺血心肌，这是一个很大程度上尚未探索的领域 在冠状循环中。总体假设是ROS在细胞凋亡中起关键和保护作用。 运动训练诱导的冠状动脉微循环血管舒张反应的恢复， 增强危险心肌的灌注和收缩功能。目标1将决定运动训练- 在慢性冠状动脉闭塞的心脏中诱导ROS产生的适应。目标2将 确定运动训练对候选来源的表达和亚细胞定位的影响， 心脏微血管内皮细胞活性氧的产生及相关调节亚基蛋白 慢性冠状动脉闭塞目标3将确定运动训练促进的适应性 在分离自心脏的小动脉中ROS介导的扩张的下游信号传导途径， 慢性冠状动脉闭塞目标4将确定运动训练的信号机制， 增强静息时和多巴酚丁胺诱导时的局部灌注和心肌收缩功能 慢性冠状动脉闭塞心脏的心肌应力。这些研究具有很高的影响力，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。的 拟议的研究将提供重要的新信息，对人类的机制有重要的了解。 缺血性心脏病，并确定ROS信号在控制健康冠状动脉血流中的作用， 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.