Endothelial dysfunction is a major contributor to the pathogenesis of coronary artery disease and a potential therapeutic target to improve myocardial perfusion in ischemic heart disease. The role of regular exercise in the improvement of endothelial dysfunction has garnered increasing attention from both researchers and clinicians as a mechanism by which myocardial perfusion and function can be substantially improved in patients with coronary artery disease. However, the mechanisms by which exercise training reverses endothelium dysfunction are not well defined. The overall goal of the research proposed in this application is to define the specific cellular/molecular mechanisms responsible for exercise training-induced improvements in endothelium function in collateral-dependent coronary arteries and arterioles of chronically occluded hearts. Our central hypothesis is that exercise training restores endothelium-dependent vasodilatation in coronary artery disease via enhanced nitric oxide bioavailability. Specifically, Specific Aim 1 will determine the effects of exercise training on cellular and molecular mechanisms responsible for endothelium-derived nitric oxide production in collateral-dependent coronary arteries and arterioles;
Specific Aim 2 will determine the effects of exercise training on the role of reactive oxygen species in agonist-mediated, nitric oxide-dependent relaxation in collateral-dependent coronary arteries and arterioles;
Specific Aim 3 will determine the effects of exercise training on the interaction of nitric oxide bioavailability and Rho-kinase activity in collateral-dependent coronary arteries of occluded hearts. To address these issues, we will determine the effects of exercise training on vascular endothelial function in the well-established porcine model of chronic coronary artery occlusion. These studies will examine functional vasomotor reactivity to endotheliumdependent vasodilators, protein and mRNA expression of enzymes and factors that contribute to endothelium function, and intracellular free calcium concentration and nitric oxide production in endothelial cells. Relevance: Coronary artery disease produces more than 50% of cardiovascular disease-related deaths, the preeminant health problem of developed countries worldwide. The research proposed in this application will determine the adaptations by which exercise/physical activity improves the function of the coronary arteries and thereby increases blood flow to compromised areas of the heart in diseased patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064931-11
Application #
7880939
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Liang, Isabella Y
Project Start
2000-07-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
11
Fiscal Year
2010
Total Cost
$353,201
Indirect Cost
Name
Texas Agrilife Research
Department
Physiology
Type
Schools of Earth Sciences/Natur
DUNS #
847205713
City
College Station
State
TX
Country
United States
Zip Code
77843
Zheng, Xiaoxu; Heaps, Cristine L; Fisher, Steven A (2015) Myosin phosphatase isoforms and related transcripts in the pig coronary circulation and effects of exercise and chronic occlusion. Microvasc Res 98:166-71
Dongaonkar, R M; Nguyen, T L; Quick, C M et al. (2015) Mesenteric lymphatic vessels adapt to mesenteric venous hypertension by becoming weaker pumps. Am J Physiol Regul Integr Comp Physiol 308:R391-9
Robles, Juan Carlos; Heaps, Cristine L (2015) Adaptations of the endothelin system after exercise training in a porcine model of ischemic heart disease. Microcirculation 22:68-78
Heaps, Cristine L; Robles, Juan Carlos; Sarin, Vandana et al. (2014) Exercise training-induced adaptations in mediators of sustained endothelium-dependent coronary artery relaxation in a porcine model of ischemic heart disease. Microcirculation 21:388-400
Xie, Wei; Parker, Janet L; Heaps, Cristine L (2013) Exercise training-enhanced, endothelium-dependent dilation mediated by altered regulation of BK(Ca) channels in collateral-dependent porcine coronary arterioles. Microcirculation 20:170-82
Deer, Rachel R; Heaps, Cristine L (2013) Exercise training enhances multiple mechanisms of relaxation in coronary arteries from ischemic hearts. Am J Physiol Heart Circ Physiol 305:H1321-31
Xie, Wei; Parker, Janet L; Heaps, Cristine L (2012) Effect of exercise training on nitric oxide and superoxide/H?O? signaling pathways in collateral-dependent porcine coronary arterioles. J Appl Physiol (1985) 112:1546-55
Robles, Juan Carlos; Sturek, Michael; Parker, Janet L et al. (2011) Ca2+ sensitization and PKC contribute to exercise training-enhanced contractility in porcine collateral-dependent coronary arteries. Am J Physiol Heart Circ Physiol 300:H1201-9
Sarin, Vandana; Muthuchamy, Mariappan; Heaps, Cristine L (2011) Ca²? sensitization of cardiac myofilament proteins contributes to exercise training-enhanced myocardial function in a porcine model of chronic occlusion. Am J Physiol Heart Circ Physiol 301:H1579-87
Heaps, Cristine L; Parker, Janet L (2011) Effects of exercise training on coronary collateralization and control of collateral resistance. J Appl Physiol (1985) 111:587-98

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