Exercise Training Endothelial Phenotype/Coronary Disease

运动训练内皮表型/冠状动脉疾病

• 批准号: 7140018
• 负责人: M HAROLD LAUGHLIN
• 金额: $ 36.76万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140018
• 关键词: atherosclerosis; cardiovascular disorder prevention; cardiovascular pharmacology; catalase; caveolins; coronary artery; coronary disorder; dietary lipid; disease /disorder model; enzyme activity; exercise; gene expression; hyperlipidemia; macrophage; miniature swine; nitric oxide; nitric oxide synthase; nutrition related tag; phenotype; prostaglandin endoperoxide synthase; shear stress; superoxide dismutase; vascular endothelium; vascular smooth muscle; vasodilation

Exercise training (EX) increases coronary blood flow capacity and alters coronary vasomotor responsiveness in normal animals. Endothelium-dependent dilation (EDO) is blunted in the left anterior descending coronary artery (LAD) of sedentary pigs (SED) with early stage coronary artery disease (CAD) produced by feeding a high fat/cholesterol diet for 5 months (HFC). EX of this HFC model of CAD restores EDO in the LAD. These interactive effects of EX and HFC diet form the foundation for the central hypothesis of Project 3: The beneficial effects of EX in prevention and treatment of CAD are mediated by restoration/maintenance of a normal coronary endothelialphenotype. Aim 1 will determine mechanisms responsible for EX-induced improvements in EDO of LADs of HFC pigs. Preliminary results indicate that EX preserves/restores EDO in HFC pigs by increasing availability of endothelium-derived NO and decreasing production of a cyclooxygenase constrictor substance. We will use pharmacological, biochemical and molecular approaches to determine whether these modifications result from altered expression of genes for enzymes/receptors responsible for EDO and/or altered activity of these enzymes. Aim 2 will determine whether mechanical signals (shear stress and stretch) produce EX like changes in expression of endothelial nitric oxide synthase (eNOS) and other protective genes in normal and diseased coronary arteries. In Aim 3 we will determine whether EX produces a more atheroprotective phenotype of endothelial and/or foam cells during early development of CAD. We will use biochemical, molecular and morphologic approaches to characterize the phenotypes of vascular cells in SED and EX arteries. Aim 4 experiments are designed to use genetically modified pigs (that over express eNOS and eNOS knock-out) to determine the role of eNOS in the interactive effects of EX and HFC on endothelial function and CAD. Available results indicate that much of the beneficial effects of EX on CAD are mediated by changes in NO release from eNOS. Aim 5 will use the protocols and techniques applied to our model of early CAD to test the hypothesis that EX also has beneficial effects on more advanced disease (2 yrs on the HFC diet). Completion of the research proposed in Project 3 will improve understanding of mechanisms for anti-atherogenic effects of EX on endothelial function and phenotype in coronary arteries and the roles of inflamation, shear stress, and distention in producing or sustaining an anti-atherogenic phenotype of endothelial and foam cells in the arterial wall. This research will provide a solid fundamental basis for understanding the effects of EX in preventing/reversing CAD and for an improved ability to use exercise in treating and prevention of CAD.

运动训练(EX)增加冠脉血流量并改变冠脉血管舒缩反应性 在正常动物身上。左前降支冠状动脉内皮依赖性扩张(EDO)钝化 高脂饲料诱导的早期冠心病(CAD)久坐猪动脉(LAD) 脂肪/胆固醇饮食5个月(HFC)。这个CAD的HFC模型的EX恢复了LAD中的EDO。这些 EX和HFC饮食的相互作用构成了项目3的中心假设的基础：有益 EX预防和治疗冠心病的作用是通过恢复/维持正常 冠状动脉内皮细胞表型。目标1将确定导致ex诱导的改进的机制 在HFC猪LAD的EDO中。初步结果表明，EX通过以下方式保存/恢复HFC猪的EDO 增加内皮源性NO的利用率和减少环氧合酶缩窄器的产生 实质性的。我们将使用药理学、生化和分子方法来确定这些 修饰是由负责EDO的酶/受体的基因表达改变和/或改变引起的 这些酶的活性。目标2将确定机械信号(剪应力和拉伸)是否会产生 正常人内皮型一氧化氮合酶等保护性基因表达的类异构体变化 以及病变的冠状动脉。在目标3中，我们将确定EX是否会产生更强的动脉粥样硬化保护作用 冠心病早期发展过程中内皮细胞和/或泡沫细胞的表型。我们将使用生物化学， 用于表征SED和EX动脉血管细胞表型的分子和形态方法。 目的用转基因猪(过度表达eNOS和enos基因敲除)进行实验4。 探讨内皮型一氧化氮合酶(ENOS)在EX和HFC对内皮细胞功能和冠心病相互作用中的作用。 现有研究结果表明，EX对冠心病的许多有益作用是通过NO的变化来实现的 从enos释放。Aim 5将使用应用于我们的早期CAD模型的协议和技术来测试 假设EX对更晚期的疾病也有有益的影响(HFC饮食2年)。完成 项目3中提出的研究将提高对抗动脉粥样硬化作用机制的理解 EX对冠状动脉内皮细胞功能和表型的影响及其在炎症、剪应力和血管病变中的作用 动脉内皮细胞和泡沫细胞产生或维持抗动脉粥样硬化表型的扩张 墙。这项研究将为理解EX的影响提供坚实的基础。 预防/逆转CAD，并提高利用运动治疗和预防CAD的能力。