Resistance Training Improvement in Age-Associated Endothelial Dysfunction

描述(申请人提供)：衰老与内皮功能下降有关，而内皮功能下降又是许多不良心血管事件的先兆。大量研究表明，耐力运动训练增强了正常人、老年人和动物的血管功能，以及在慢性心力衰竭、冠状动脉疾病、高血压、高胆固醇血症、肥胖和糖尿病等病理条件下的血管功能。尽管有证据表明运动可以改善老年模型的血管功能，但很少有研究考察阻力训练对血管功能的影响。此外，检验阻力训练效果的少数研究主要涉及人类受试者，在这些受试者中，内皮功能改善的分子机制尚未确定。耐力运动改善血管功能的主要分子机制之一被认为是减少超氧化物的形成和伴随的NO生物利用度的增加。根据这些观察，我们将检查8周的大鼠阻力训练计划是否会改善老年动物的主动脉、股动脉和阻力小动脉的NO依赖性血管松弛，使用分离的血管环和加压血管准备。此外，我们将研究这些血管中超氧化物形成和蛋白质酪氨酸硝化的变化，以确定耐力运动等阻力运动是否减少了血管氧化应激。还将使用超氧化物的药物抑制剂和超氧化物形成的措施来探索产生超氧化物和氧化应激的潜在细胞来源。最后，我们将检验eNOS表达的变化或eNOS的翻译后修饰是否可以解释通过免疫共沉淀和免疫印迹的方法改善阻力训练、老年大鼠血管内皮细胞功能和减少氧化应激的原因。目的1.验证阻力运动训练可改善不同血管床年龄相关性内皮功能障碍的假说。目的2.验证抵抗力运动降低幼年和老年动物血管氧化应激的假设。目的3.验证这一假说，即一氧化氮合酶的表达增加和eNOS的翻译后修饰在慢性阻力运动训练过程中是瞬时改变的。 公共卫生相关性：心血管疾病是美国和世界范围内的主要死亡原因，患心血管疾病的风险随着年龄的增长而增加。衰老还与肌肉力量和活动能力的下降有关，这可以通过抗阻运动训练来预防；然而，这种类型的训练是否也像耐力训练一样可以降低心血管疾病的风险还不清楚。该项目将研究阻力运动训练可以降低与年龄增长相关的心血管疾病风险的潜在机制。

DESCRIPTION (provided by applicant): Aging is associated with a decline in endothelial function which in-turn is a precursor to many adverse cardiovascular events. Numerous studies have shown that endurance exercise training enhances vascular function in both normal and aged humans and animals as well as under pathological conditions such as chronic heart failure, coronary artery disease, hypertension, hypercholesterolemia, obesity, and diabetes. Despite the evidence for exercise-induced improvements in vascular function in aged models, few of these studies have examined the effects of resistance training on vascular function. In addition, the few studies examining the effects of resistance training have primarily involved human subjects in which the molecular mechanisms of the improved endothelial function were not determined. One of the primary molecular mechanisms believed to play a role in endurance exercise induced improvement in vascular function is a decrease in superoxide formation and a concomitant increase in NO bioavailability. In light of these observations we will examine whether an 8 week resistance training program in rats will improve NO- dependent vasorelaxation in the aorta, femoral and resistance arterioles of aged animals using isolated vascular rings and cannulated, pressurized vessel preparations. Furthermore, we will examine changes in superoxide formation and protein tyrosine nitration in these vessels to determine if resistance exercise like endurance exercise reduces vascular oxidative stress. Potential cellular sources of superoxide generation and oxidative stress will also be explored using pharmacological inhibitors of superoxide and measures of superoxide formation. Finally, we will examine whether changes in eNOS expression or posttranslational modifications of eNOS can account for the improvements in endothelial function and reduction of oxidative stress in vessels from resistance trained, aged rats using co-immunoprecipitation and immunoblotting of these vascular tissues. Aim 1. To test the hypothesis that resistance exercise training will improve age-associated endothelial dysfunction in different vascular beds. Aim 2. To test the hypothesis that resistance exercise reduces vascular oxidative stress in young and old animals. Aim 3. To test the hypothesis that increases in NOS expression and posttranslational modifications of eNOS are transiently altered over the course of a chronic resistance exercise training program. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death in the United States and worldwide and the risk of having cardiovascular disease increases with age. Aging is also associated with a decline in muscular strength and mobility which can be prevented by resistance exercise training; however, it is unknown whether this type of training like endurance training can also reduce the risk of cardiovascular disease. This project will examine potential mechanisms by which resistance exercise training can reduce the risk of cardiovascular disease associated with advancing age.