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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结