Chronic coronary occlusion, exercise training and NO

描述(申请人提供)：内皮功能障碍是冠状动脉疾病发病机制的主要因素，也是改善缺血性心脏病心肌灌注的潜在治疗目标。有规律的运动在改善内皮功能障碍中的作用越来越受到研究人员和临床医生的关注，因为它是一种显著改善冠心病患者心肌灌注和功能的机制。然而，运动训练逆转内皮功能障碍的机制尚不清楚。本申请中提出的研究的总体目标是确定运动训练导致慢性闭塞心脏侧支依赖的冠状动脉和小动脉内皮功能改善的具体细胞/分子机制。我们的中心假设是，运动训练通过增强一氧化氮的生物利用度来恢复冠心病患者的内皮依赖性血管扩张。具体地说，特定目标1将确定运动训练对侧支依赖冠状动脉和小动脉内皮源性一氧化氮产生的细胞和分子机制的影响；特定目标2将确定运动训练对激动剂介导的依赖侧支循环的一氧化氮依赖的冠状动脉和小动脉中活性氧的作用的影响；特定目标3将确定运动训练对闭塞心脏侧支依赖的冠状动脉中一氧化氮生物利用度和Rho-K活性相互作用的影响。为了解决这些问题，我们将在已建立的猪慢性冠状动脉闭塞模型中确定运动训练对血管内皮功能的影响。这些研究将检测功能性血管舒张剂对内皮依赖性血管扩张剂的反应性，促进内皮功能的酶和因子的蛋白质和mRNA表达，以及内皮细胞内游离钙浓度和一氧化氮的产生。相关性：心血管疾病相关死亡的50%以上是由冠状动脉疾病造成的，这是全球发达国家的首要健康问题。在这项申请中提出的研究将确定运动/体力活动改善冠状动脉功能从而增加疾病患者心脏受损区域的血流量的适应。

DESCRIPTION (provided by applicant): 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.