Exercise Training-Enhanced Reactive Oxygen Species as Protective Mechanisms in the Coronary Microcirculation
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Project SummaryRegular exercise is a proven, powerful and cost-effective intervention for the treatment and secondaryprevention of coronary artery disease. However, a detailed understanding of the fundamental cellular andmolecular mechanisms that underlie exercise-induced cardioprotection are lacking, limiting the development ofeffective new therapeutic strategies for diseased patients. Despite recent advances in the appreciation ofreactive oxygen species (ROS) as critical regulators of cell signaling, the details of the specific contributions ofthese molecules to physiologic signaling and functional adaptions in the vascular system remain to beelucidated. This is particularly true in the coronary microcirculation where studies determining the contributionsof ROS in the control of blood flow are sparse. The proposed studies will utilize a combination of in vitro and invivo approaches to determine how exercise-induced adaptations in ROS signaling affect vascular reactivityand coronary blood flow into both control and ischemic myocardium, an area that has been largely unexploredin the coronary circulation. The overarching hypothesis is that ROS play a critical and protective role in theexercise training-induced restoration of vasodilation responses in the coronary microcirculation and therebyenhances 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 willdetermine the effects of exercise training on the expression and subcellular localization of candidate sources ofROS production and associated regulatory subunit proteins in microvascular endothelium of hearts subjectedto chronic coronary artery occlusion. Aim 3 will identify the adaptations by which exercise training promotesdownstream signaling pathway(s) for ROS-mediated dilation in arterioles isolated from hearts subjected tochronic coronary artery occlusion. Aim 4 will identify the signaling mechanisms by which exercise trainingenhances regional perfusion and myocardial contractile function at rest and during dobutamine-inducedmyocardial stress in hearts subjected to chronic coronary occlusion. These studies are of high impact since theknowledge gained will provide novel insight into the protective role of ROS in the cardiovascular system. Theproposed studies will provide important new information with significant mechanistic insight into humanischemic heart disease and identify the role of ROS signaling in the control of coronary blood flow in health,disease, and exercise adaptation.