MitoQ supplementation for restoring aerobic exercise training effects on endothelial function in postmenopausal women

补充 MitoQ 恢复有氧运动训练对绝经后女性内皮功能的影响

基本信息

批准号：
10686453
负责人：
Kerrie Moreau
金额：
$ 43万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686453
关键词：
Acetylcholine Action Research Acute Aerobic Exercise Age Aging Antioxidants Ascorbic Acid Biological Availability Biopsy Blood Vessels Blood flow Cardiovascular Diseases Cause of Death Cells Clinical Clinical Trials Death Rate Development Effectiveness Elderly Endothelial Cells Endothelium Estrogens Etiology Exercise Forearm Foundations Health Human Infusion procedures Intervention Life Style Link Measures Mediating Menopause Mitochondria Mus Nitric Oxide Oral Oral Administration Oxidative Stress Pharmacology Physiological Placebos Population Postmenopause Process Production Randomized Controlled Trials Reactive Oxygen Species Role Secondary to Serum Signal Transduction Supplementation Therapeutic Therapeutic Intervention Umbilical vein Vascular Endothelial Cell Vascular Endothelium Woman antioxidant enzyme base brachial artery cardioprotection cardiovascular disorder prevention cardiovascular disorder risk cardiovascular risk factor efficacy testing endothelial dysfunction evidence base evidence based guidelines exercise program exercise training hormone therapy improved in vivo insight male men middle age mitoquinone mortality novel older men older women post intervention preservation prevent response sex

项目摘要

PROJECT SUMMARY/ABSTRACT Endothelial dysfunction is a critical factor in the etiology of age-associated cardiovascular disease (CVD), the leading cause of death in postmenopausal women. Regular aerobic exercise (AE) enhances macro- and micro-vascular endothelial function in older men by reducing oxidative stress and preserving nitric oxide (NO) bioavailability, however, similar AE training improvements are diminished or absent in estrogen (E2)-deficient postmenopausal women. NO-mediated endothelial function and oxidative stress are improved with AE training in postmenopausal women treated with E2, suggesting an essential role of E2 in endothelial adaptations to AE in women. Clinical use of E2 is contraindicated for this purpose, thus establishing alternative pharmacological approaches that could be administered as a substitute for E2 to transduce AE signaling for vascular endothelial benefits and reducing CVD risk in E2-deficient postmenopausal women is biomedically important. The mitochondrial-targeted antioxidant MitoQ may be an alternative to E2 for restoring AE-endothelial signaling in E2-deficient postmenopausal women given its recently established effectiveness for reducing reactive oxygen species (ROS) and oxidative stress and improving endothelial function in that population. Accordingly, the overall aim of this application is to assess the efficacy of a 12-week randomized controlled trial of moderate intensity AE training combined with oral MitoQ (20 mg/d) compared to AE+oral placebo (PL) or No AE+MitoQ on macrovascular (brachial artery flow-mediated dilation; FMDBA) and microvascular (forearm blood flow response to intra-brachial infusion of acetylcholine; FBFAch) endothelial function in healthy E2-deficient postmenopausal women. Mechanistic insight related to NO bioavailability, mitochondrial function, ROS/oxidative stress, and the influence of “circulating factors” will also be obtained. We hypothesize that AE+MitoQ will improve both FMDBA and FBFAch > AE+PL and > No AE+MitoQ, and that No AE+MitoQ will improve FMDBA and FBFAch > AE+PL. The greater improvements in endothelial function with AE+MitoQ vs. both AE+PL and No AE+MitoQ, and with No AE+MitoQ vs. AE+PL will be mediated by greater improvements in NO bioavailability, mitochondrial function, and mitochondrial and whole cell ROS-related suppression of endothelial function linked, at least in part, to changes in “circulating factors”. The expected results from this study will establish the efficacy of MitoQ for restoring AE-endothelial signaling in E2-deficient postmenopausal women, and will provide the foundation for development of evidence-based guidelines for sex-specific AE programs for improving vascular health and preventing CVD in postmenopausal women.

项目概要/摘要内皮功能障碍是年龄相关性心血管疾病（CVD）病因学的一个关键因素定期有氧运动 (AE) 可以增强宏观和健康水平，是绝经后妇女死亡的主要原因。通过减少氧化应激和保护一氧化氮 (NO) 来维持老年男性的微血管内皮功能然而，在雌激素 (E2) 缺乏的情况下，类似的 AE 训练改善效果会减弱或不存在绝经后女性通过 AE 训练可以改善 NO 介导的内皮功能和氧化应激。在接受 E2 治疗的绝经后妇女中，表明 E2 在内皮适应 AE 中发挥重要作用女性中 E2 的临床使用是禁忌的，因此建立了替代药理学。可以作为 E2 的替代品来转导血管内皮细胞的 AE 信号的方法 E2 缺乏的绝经后妇女的益处和降低 CVD 风险具有重要的生物医学意义。线粒体靶向抗氧化剂 MitoQ 可能是 E2 的替代品，用于恢复 AE 内皮信号传导鉴于 E2 最近确定的减少活性氧的功效，因此缺乏 E2 的绝经后妇女物种（ROS）和氧化应激并改善该人群的内皮功能。该应用程序的总体目标是评估一项为期 12 周的随机对照试验的有效性与 AE+口服安慰剂 (PL) 或无 AE+MitoQ 相比，强度 AE 训练结合口服 MitoQ（20 mg/d）对大血管（肱动脉血流介导的扩张；FMDBA）和微血管（前臂血流健康 E2 缺乏者对臂内注射乙酰胆碱的反应；绝经后妇女与一氧化氮生物利用度、线粒体功能相关的机制见解。 ROS/氧化应激，以及“循环因素”的影响也将被我们捕获。 AE+MitoQ 将改善 FMDBA 和 FBFAch > AE+PL 和 > 无 AE+MitoQ，并且无 AE+MitoQ 将改善改善 FMDBA 和 FBFAch > AE+PL 与 AE+MitoQ 相比，内皮功能改善更大。 AE+PL 和无 AE+MitoQ，以及无 AE+MitoQ 与 AE+PL 相比，将通过更大的改进来调节 NO 生物利用度、线粒体功能以及线粒体和全细胞 ROS 相关的抑制内皮功能至少部分与“循环因子”的变化有关。研究将确定 MitoQ 在 E2 缺乏的绝经后恢复 AE 内皮信号传导的功效女性，并将为制定针对特定性别 AE 的循证指南奠定基础改善绝经后妇女血管健康和预防心血管疾病的计划。