Human Aging, Exercise & FMD: Translational Physiology

人类衰老、运动

• 批准号: 6945863
• 负责人: DOUGLAS R SEALS
• 金额: $ 28.35万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6945863
• 关键词: aerobic exercise; aging; artery; blood chemistry; cardiovascular disorder therapy; cardiovascular function; clinical research; clinical trials; enzyme activity; human middle age (35-64); human old age (65+); human subject; human therapy evaluation; immunofluorescence technique; nitric oxide; nitric oxide synthase; nutrition related tag; oxidative stress; photon absorptiometry; statistics /biometry; sympathetic nervous system; tetrahydrobiopterin; urinalysis; vascular resistance; vasodilation

DESCRIPTION(provided by applicant): This is a competitive renewal proposal for R01 AG13038, currently in its 8th consecutive year of funding. The focus of this award has been to study the effects of aging and lifestyle interventions on large artery function and structure. In the present plan we propose to continue our productive work on this theme by testing the following tightly focused set of working hypotheses: 1) regular moderate-intensity aerobic exercise (daily brisk walking) increases peripheral conduit artery flow-mediated dilation (FMD), a measure of endothelium-dependent vasodilatory capacity and overall arterial vascular health, in previously sedentary middle-aged and older adults; 2) an increase in nitric oxide (NO) bioavailability is the key mechanism by which regular aerobic exercise improves FMD; 3) an increase in the bioavailability of the critical co-factor for NO synthesis, tetrahydrobiopterin (BH4), is one mechanism by which regular aerobic exercise increases NO bioavailability and FMD; 4) a reduction in vascular oxidative stress, related in part to an increase in extracellular superoxide dismutase (ecSOD), is an important mechanism by which regular aerobic exercise increases BH4 and NO bioavailability and FMD; 5) changes in the expression of proteins encoded by specific genes in arterial endothelial cells (i.e., increases in enzymatic antioxidant, eNOS, and phosphorylated eNOS protein expressions, and reductions in oxidant enzyme, endothelin-1, and angiotensin II receptor protein expressions) are among the key molecular mechanisms associated with the favorable effects of regular aerobic exercise on oxidative stress, BH4 and NO bioavailability, and FMD. To test these hypotheses we will conduct 2 complementary randomized aerobic exercise intervention trials in sedentary healthy middle-aged and older (age 55-75 years) men and women. The mechanistic roles played by changes in vascular oxidative stress and BH4 and NO bioavailability in mediating improvements in FMD will be determined in experimental sessions conducted before and after a 12-week exercise (or non-exercise attention control) condition. Insight into the molecular mechanisms involved will be obtained using a novel translational physiology research technique by which changes in arterial endothelial cell protein expression of genes involved in the regulation of these cellular and systemic adaptations to habitual exercise will be determined via quantitative immunofluorescence. The expected results will provide new, clinically important insight into the efficacy of moderate aerobic exercise for restoring arterial endothelial function in middle-aged and older sedentary adults, and the underlying mechanisms. In particular, the proposed research will provide the first information on 2 highly novel mechanisms by which regular exercise may augment NO bioavailability: 1) by increasing BH4 bioavailability; and 2) by producing changes in the expression of key arterial endothelial cell proteins involved in determining endothelial function.

描述（由申请人提供）：这是R01 AG13038的竞争续订提案，目前连续第8年获得资金。该奖项的重点是研究衰老和生活方式干预对大动脉功能和结构的影响。在本计划中，我们建议通过测试以下紧密集中的工作假设来继续我们的富有成效的工作：1）定期的中度强度有氧运动（每天轻快步行）增加外围导管流动动脉流动介导的扩张（FMD），衡量了依赖于内皮性的血管降压性血管降压和较老的，以前是既依赖于内皮的血管疾病，以前是既扎根又有既定的，以前又是扎实的，以前; 2）一氧化氮（NO）生物利用度增加是定期有氧运动改善FMD的关键机制； 3）关键辅助因素无合成的生物利用度增加，四氢蛋白酶蛋白（BH4）是一种机制，通过这种机制，常规有氧运动不增加生物利用度和FMD。 4）血管氧化应激的减少，部分与细胞外超氧化物歧化酶（ECSOD）的增加有关，是一种重要的机制，正常有氧运动可以增加BH4，而无生物利用度和FMD； 5）5）动脉内皮细胞中特定基因编码的蛋白质表达的变化（即增加酶抗氧化剂，eNOS和磷酸化的ENOS蛋白表达的酶，氧化剂酶的氧化酶，氧化剂蛋白质的降低，以及与血管素II受体蛋白质表达相关的氧化酶的氧化酶的氧化剂的降低）压力，BH4和无生物利用度和FMD。为了检验这些假设，我们将对久坐健康的中年和年龄较大（55-75岁）的男性和女性进行2项互补的随机有氧运动干预试验。血管氧化应激和BH4的变化所扮演的机械作用，以及在介导FMD改进中的生物利用度，将在进行12周运动（或非锻炼注意力控制）条件之前和之后进行的实验会议中确定。将使用一种新型的翻译生理研究技术获得对所涉及分子机制的洞察力，通过该技术，该技术的变化将通过定量免疫荧光来确定参与调节这些细胞和全身适应习惯运动的基因的基因表达。预期的结果将为中年和久违的成年人以及基本机制恢复中等有氧运动的疗效提供新的，临床上重要的见解。尤其是，拟议的研究将提供有关2种高度新颖机制的第一个信息，通过这些信息可以定期进行不增强生物利用度：1）通过增加BH4生物利用度； 2）通过产生与确定内皮功能有关的关键动脉内皮细胞蛋白表达的变化。