Chronic coronary occlusion, exercise training and NO

慢性冠状动脉闭塞、运动训练与NO

• 批准号: 7099840
• 负责人: CRISTINE L HEAPS
• 金额: $ 36.38万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099840
• 关键词: arterioles; calcium flux; cardiovascular function; chronic disease /disorder; coronary artery; coronary occlusion /thrombosis; enzyme activity; exercise; free radical oxygen; heart circulation; miniature swine; nitric oxide; serine threonine protein kinase; vascular endothelium; vasodilation

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.

描述（由申请人提供）：内皮功能障碍是冠状动脉疾病发病机制的主要原因，也是改善缺血性心脏病心肌灌注的潜在治疗靶点。定期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，作为一种可以显着改善冠状动脉疾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明确。本申请提出的研究的总体目标是确定负责运动训练诱导的慢性闭塞心脏的侧支依赖性冠状动脉和小动脉内皮功能改善的特定细胞/分子机制。我们的中心假设是运动训练通过增强一氧化氮生物利用度来恢复冠状动脉疾病中内皮依赖性血管舒张。具体来说，具体目标 1 将确定运动训练对侧支依赖性冠状动脉和小动脉中负责内皮衍生一氧化氮生成的细胞和分子机制的影响；具体目标 2 将确定运动训练对活性氧在侧支依赖性冠状动脉和小动脉中激动剂介导的、一氧化氮依赖性松弛中的作用的影响；具体目标 3 将确定运动训练对闭塞心脏侧支依赖性冠状动脉中一氧化氮生物利用度和 Rho 激酶活性相互作用的影响。为了解决这些问题，我们将在成熟的慢性冠状动脉闭塞猪模型中确定运动训练对血管内皮功能的影响。这些研究将检查内皮依赖性血管舒张剂的功能性血管舒缩反应性、有助于内皮功能的酶和因子的蛋白质和 mRNA 表达，以及内皮细胞中的细胞内游离钙浓度和一氧化氮的产生。相关性：超过 50% 的心血管疾病相关死亡是由冠状动脉疾病造成的，心血管疾病是全世界发达国家面临的首要健康问题。本申请中提出的研究将确定运动/体力活动如何改善冠状动脉功能，从而增加流向患病患者心脏受损区域的血流量。