Reduced Inflammatory Suppression of EDD with Habitual Exercise in Older Adults

描述(由申请人提供)：这项修改后的申请寻求支持旨在治疗人类血管老化的新工作。这项拟议的研究将确定，习惯性有氧运动是否通过减少紧张性炎症和氧化应激介导的EDD抑制来改善中老年人的内皮依赖性扩张(EDD)，EDD是血管内皮功能和心血管疾病风险的临床重要标志。这项拟议的工作还将为有规律的有氧运动改善紧张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。综合工作假说：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的改善将与减少紧张性炎症介导的EDD抑制有关。后者又将与：7全身性促炎“环境”减少，特征是细胞因子和其他炎症介质的血浆促炎/抗炎浓度降低7 a炎性血管内皮细胞表型减少，7血管内皮细胞促炎/抗炎细胞因子蛋白表达减少7血管内皮细胞激活关键的炎性转录因子核因子B(NF：B)，与控制其激活和核转位的蛋白质变化有关。EDD紧张性炎症相关抑制的减少将与氧化应激介导的EDD抑制的减少有关。后者又与以下因素有关：7全身氧化应激减少7氧化作用减弱的血管内皮细胞表型，部分特征是氧化酶和氧化修饰蛋白在血管内皮细胞中的表达减少。实验方法：我们将进行为期12周的有氧运动干预(随机设计，注意力控制)。炎症对EDD的紧张性影响将在干预期前后通过口服水杨酸盐对短期阻断NF：B信号的EDD的改善来确定。氧化应激的影响将通过急性服用抗坏血酸(维生素C)时EDD的增加来评估，维生素C是一种有效的抗氧化剂。主要结果将包括肱动脉血流介导的扩张(EDD)和全身和/或血管内皮炎症的测量，核因子：B相关蛋白，氧化应激，以及氧化和抗氧化酶。公共卫生相关性：这项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有规律的有氧运动是否能改善中老年男性和女性的动脉功能，如果是的话，炎症状态的减轻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.