Reduced Inflammatory Suppression of EDD with Habitual Exercise in Older Adults

描述（由申请人提供）：本修订后的申请寻求支持旨在治疗人类血管衰老的新工作。拟议的研究将确定是否习惯性有氧运动改善内皮依赖性扩张（EDD），血管内皮功能和心血管疾病风险的临床重要标志，在中/老年人通过减少强张性炎症和氧化应激介导的EDD抑制。这项工作也将为有规律的有氧运动可能改善强直性炎症和氧化应激介导的EDD抑制的细胞和分子机制提供新的见解。综合工作假设：在以前久坐不动的健康中老年（60-79岁）男性和女性中，习惯性有氧运动对EDD的改善将与炎症介导的EDD抑制减少有关。后者又将涉及：7 .全身性促炎“环境”减少，其特征是促炎/抗炎细胞因子和其他炎症介质的血浆浓度降低；7 .炎性血管内皮表型减少，其特征是促炎/抗炎细胞因子蛋白在血管内皮中的表达减少；7 .血管内皮中关键炎症转录因子、核因子的激活减少；B (NF:B)，与控制其激活和核易位的蛋白质变化有关。强直性炎症相关的EDD抑制减少与氧化应激介导的EDD抑制减少有关。反过来，后者将与：7减少系统性氧化应激7减少促氧化血管内皮表型有关，其部分特征是血管内皮中氧化酶和氧化修饰蛋白表达减少。实验方法：我们将进行为期12周的有氧运动干预（随机设计，注意控制）。通过口服水杨酸盐短期阻断NF:B信号后EDD的改善，可以确定炎症对EDD的补剂作用在干预期前后。氧化应激的影响将通过急性给予抗坏血酸（维生素C）（一种有效的抗氧化剂）后EDD的增加来评估。主要结果将包括肱动脉血流介导的扩张（EDD）和全身和/或血管内皮炎症、NF: b相关蛋白、氧化应激、氧化酶和抗氧化酶的测量。公共卫生相关性：本申请寻求支持旨在治疗成人动脉老化的新研究。这项拟议的研究将确定定期有氧运动是否能改善中老年男性和女性的动脉功能，如果是这样，炎症状态的减少是否是运动有益效果的主要原因。

DESCRIPTION (provided by applicant): This amended application seeks support for new work aimed at the treatment of vascular aging in humans. The proposed research will determine if habitual aerobic exercise improves endothelium-dependent dilation (EDD), a clinically important marker of vascular endothelial function and cardiovascular disease risk, in middle- aged/older adults by reducing tonic inflammation- and oxidative stress-mediated suppression of EDD. The proposed work also will provide novel insight into the cellular and molecular mechanisms by which regular aerobic exercise may improve tonic inflammation- and oxidative stress-mediated suppression of EDD. Integrative Working Hypothesis: In previously sedentary healthy middle-aged/older (60-79 years) men and women, the improvements in EDD in response to habitual aerobic exercise will be associated with reduced tonic inflammation-mediated suppression of EDD. The latter will, in turn, be related to: 7 a reduced systemic pro-inflammatory "milieu", characterized by decreased pro-inflammatory/increased anti-inflammatory plasma concentrations of cytokines and other inflammatory mediators 7 a reduced inflammatory vascular endothelial phenotype, characterized by decreased pro-inflammatory/ increased anti-inflammatory cytokine protein expression in the vascular endothelium 7 reduced vascular endothelial activation of the key inflammatory transcription factor, nuclear factor : B (NF:B), associated with changes in the proteins controlling its activation and nuclear translocation. The reduced tonic inflammation-related suppression of EDD will be associated with decreased oxidative stress-mediated inhibition of EDD. The latter will, in turn, be related to: 7 reduced systemic oxidative stress 7 a less pro-oxidant vascular endothelial phenotype, characterized in part by decreased oxidant enzyme and oxidation-modified protein expression in the vascular endothelium. Experimental Approach: We will conduct a 12-week aerobic exercise intervention (randomized design with attention control). The tonic influence of inflammation on EDD will be determined before and after the intervention period by the improvement in EDD in response to short-term blockade of NF:B signaling with orally administered Salsalate. The effects of oxidative stress will be assessed by the increase in EDD in response to acute administration of ascorbic acid (vitamin C), a potent antioxidant. Key outcomes will include brachial artery flow-mediated dilation (EDD) and measures of systemic and/or vascular endothelial inflammation, NF:B-related proteins, oxidative stress, and oxidant and antioxidant enzymes. PUBLIC HEALTH RELEVANCE: This application seeks support for new research aimed at the treatment of aging of the arteries in adults. The proposed research will determine if regular aerobic exercise improves the function of the arteries in middle- aged/older men and women and, if so, if a reduction in the state of inflammation is a major reason for the beneficial effects of exercise.