Reduced Inflammatory Suppression of EDD with Habitual Exercise in Older Adults

通过老年人的习惯性运动减少 EDD 的炎症抑制

• 批准号: 7937926
• 负责人: DOUGLAS R SEALS
• 金额: $ 49.41万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937926
• 关键词: Acute; Acute-Phase Proteins; Adult; Aerobic Exercise; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Arteries; Ascorbic Acid; Attention; Blood Vessels; Clinical; Complement Factor B; Disease; Elderly; Endothelium; Enzymes; Exercise; Human; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Life; Measures; Mediating; Molecular; Nuclear; Nuclear Translocation; Outcome; Oxidants; Oxidative Stress; Phenotype; Plasma; Proteins; Randomized; Reactive Oxygen Species; Research; Signal Transduction; Vascular Endothelium; Woman; Work; aged; brachial artery; cardiovascular disorder risk; chemokine; cytokine; design; disorder risk; genetic regulatory protein; improved; improved functioning; inflammatory marker; insight; men; middle age; novel; older men; oxidation; primary outcome; protein expression; public health relevance; response; salicylsalicylic acid; secondary outcome; sedentary; transcription factor; urinary

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.

描述（由申请人提供）：本修订后的申请寻求对旨在治疗人类血管老化的新工作的支持。拟议的研究将确定习惯性有氧运动是否可以通过减少强直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。这项工作还将提供对细胞和分子机制的新见解，通过这些机制，定期有氧运动可以改善强直性炎症和氧化应激介导的 EDD 抑制。综合工作假设：在以前久坐的健康中年/老年（60-79岁）男性和女性中，习惯性有氧运动对EDD的改善将与强直性炎症介导的EDD抑制的减少有关。后者又与： 7 全身促炎“环境”减少，其特征是细胞因子和其他炎症介质的促炎/抗炎血浆浓度降低 7 炎症血管内皮表型减少，其特征是血管内皮中促炎/抗炎细胞因子蛋白表达减少 7 关键炎症转录因子核因子 : B (NF:B) 的血管内皮激活减少，与控制其激活和核转位的蛋白质变化相关。 EDD 的强直性炎症相关抑制的减少与氧化应激介导的 EDD 抑制的减少有关。后者又与： 7 全身氧化应激减少 7 促氧化血管内皮表型减少，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）。炎症对 EDD 的强直影响将通过口服双水杨酯短期阻断 NF:B 信号后 EDD 的改善来确定干预期之前和之后的情况。氧化应激的影响将通过紧急施用抗坏血酸（维生素 C）（一种有效的抗氧化剂）引起的 EDD 增加来评估。主要结果包括肱动脉血流介导的扩张 (EDD) 以及全身和/或血管内皮炎症、NF:B 相关蛋白、氧化应激以及氧化剂和抗氧化酶的测量。公共健康相关性：本申请寻求对旨在治疗成人动脉老化的新研究的支持。拟议的研究将确定定期有氧运动是否可以改善中年/老年男性和女性的动脉功能，如果可以，炎症状态的减轻是否是运动产生有益效果的主要原因。