Human Aging, Exercise & FMD: Translational Physiology

这是R 01 AG 13038的竞争性更新提案，目前正处于连续8“年的资助期。的 该奖项的重点是研究衰老和生活方式干预对大动脉功能的影响， 结构在本计划中，我们提议继续就这一主题开展富有成效的工作，测试以下内容 一组密切关注的工作假设：1）定期中等强度的有氧运动（每天快走） 增加外周管道动脉血流介导的舒张（FMD）， 血管舒张能力和整体动脉血管健康，在以前久坐的中年和老年人; 2） 一氧化氮（NO）生物利用度的增加是规律有氧运动改善的关键机制。 FMD; 3）增加用于NO合成的关键辅因子四氢生物蝶呤（BH 4）的生物利用度是一个 定期有氧运动增加NO生物利用度和FMD的机制; 4）减少血管紧张素转换酶的表达， 氧化应激，部分与细胞外超氧化物歧化酶（ecSOD）的增加有关，是一个重要的 定期有氧运动增加BH 4和NO生物利用度和FMD的机制; 5） 由动脉内皮细胞中的特定基因编码的蛋白质的表达（即，增加酶抗氧化剂， eNOS和磷酸化eNOS蛋白表达，以及氧化酶、内皮素-1和 血管紧张素II受体蛋白表达）是与有利的 定期有氧运动对氧化应激、BH 4和NO生物利用度以及FMD的影响。测试这些 假设我们将在久坐不动的健康人群中进行2项补充随机有氧运动干预试验， 中年和老年（55-75岁）男性和女性。血管内皮细胞的变化所起的机制作用 氧化应激和BH 4和NO生物利用度在介导FMD改善中的作用将在 在12周的运动（或非运动注意力控制）条件之前和之后进行的实验会话。 深入了解所涉及的分子机制将获得使用一种新的翻译生理学研究 这项技术通过改变动脉内皮细胞蛋白质表达的基因参与调节， 这些对习惯性运动的细胞和系统适应将通过定量免疫荧光测定。 预期的结果将提供新的，临床上重要的洞察力的疗效，适度的有氧运动， 恢复中老年人久坐不动的动脉内皮功能及其潜在机制。 特别是，拟议的研究将提供有关2种高度新颖机制的第一批信息， 定期运动可以增加NO的生物利用度：1）通过增加BH 4的生物利用度; 2）通过产生 参与决定内皮功能的关键动脉内皮细胞蛋白表达的变化。 ：_省略。 科罗拉多大学博尔德分校，博尔德，科罗拉多

This is a competitive renewal proposal for R01 AG13038, currently in its 8'" 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. :_OVIDED. University of Colorado-Boulder, Boulder, Colorado