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

运动训练增强活性氧作为冠状动脉微循环的保护机制

• 批准号: 9914125
• 负责人: CRISTINE L HEAPS
• 金额: $ 60.33万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914125
• 关键词: Affect; Agonist; Angiography; Area; Automobile Driving; Biochemical; Biology; Blood Vessels; Blood flow; Calcium; Cardiac; Cardiovascular system; Cause of Death; Cells; Chronic; Coronary; Coronary Arteriosclerosis; Coronary Circulation; Coronary Occlusions; Cyclic AMP-Dependent Protein Kinases; Data; Development; Dimerization; Disease; Dobutamine; Electron Microscopy; Electron Spin Resonance Spectroscopy; Endothelial Cells; Endothelium; Evaluation; Exercise; Family suidae; Fluorescence Resonance Energy Transfer; Goals; Health; Healthcare; Heart; Heart Diseases; Human; Hydrogen Peroxide; Immunofluorescence Immunologic; In Vitro; Knowledge; Label; Left; Measures; Mediating; Microcirculation; Microspheres; Mitochondria; Modeling; Molecular; Myocardial; Myocardial Ischemia; Myocardial perfusion; Myocardium; Myosin Light Chains; NADPH Oxidase; Pathway interactions; Patients; Perfusion; Pharmacology; Physical activity; Physiological; Play; Potassium Channel; Prevention; Production; Productivity; Protein Dephosphorylation; Protein Isoforms; Protein Subunits; Proteins; Quality of life; Quantitative Reverse Transcriptase PCR; Reactive Oxygen Species; Regional Perfusion; Reporting; Rest; Risk; Role; Secondary Prevention; Signal Pathway; Signal Transduction; Small Interfering RNA; Source; Stress; Superoxides; Therapeutic; Transfection; Vascular System; Vasodilation; Ventricular; Woman; Workload; arteriole; base; cardioprotection; cofactor; coronary artery occlusion; cost; cost effective; effective intervention; exercise training; experimental study; heart function; improved; in vivo; insight; men; multidisciplinary; new therapeutic target; novel; novel therapeutic intervention; patch clamp; response; restoration; sedentary; vascular contributions; voltage

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.

项目概要 定期锻炼是一种行之有效的、有效的、具有成本效益的治疗和继发性干预措施。 预防冠状动脉疾病。然而，对基本细胞和 缺乏运动诱导的心脏保护作用的分子机制，限制了运动的发展 为患病患者提供有效的新治疗策略。尽管最近人民币升值取得了进展 活性氧（ROS）作为细胞信号传导的关键调节剂，详细介绍了其具体贡献 这些分子对血管系统的生理信号传导和功能适应仍有待研究 阐明了。在冠状动脉微循环中尤其如此，研究确定了冠状动脉微循环的贡献 控制血流的 ROS 很少。拟议的研究将结合体外和体内 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 冠状动脉血流流入对照心肌和缺血心肌，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 运动训练诱导冠状动脉微循环血管舒张反应的恢复，从而 增强高危心肌的灌注和收缩功能。目标1将确定运动训练- 诱导慢性冠状动脉闭塞心脏中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 心脏微血管内皮中ROS的产生和相关调节亚基蛋白 导致慢性冠状动脉闭塞。目标 3 将确定运动训练促进的适应性 从心脏分离的小动脉中ROS介导的扩张的下游信号通路 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期间的局部灌注和心肌收缩功能 慢性冠状动脉闭塞的心脏的心肌应激。这些研究具有很高的影响力，因为 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 拟议的研究将提供重要的新信息，对人类产生重要的机制洞察 缺血性心脏病并确定 ROS 信号在健康冠状动脉血流控制中的作用， 疾病、运动适应等。