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

项目摘要/摘要 内皮功能障碍是年龄相关性心血管疾病(CVD)病因学的关键因素 绝经后妇女死亡的主要原因。有规律的有氧运动(AE)可增强宏观和 老年男性通过减少氧化应激和保护一氧化氮(NO)实现微血管内皮细胞功能 然而，在雌激素(E2)缺乏的患者中，类似的AE训练改进减少或不存在 绝经后的女性。声发射训练改善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，提示E2在血管内皮细胞对AE的适应中起重要作用 在女人身上。为此目的，禁止临床使用雌二醇，从而建立替代药理 可替代雌二醇转导血管内皮细胞AE信号的途径 对绝经后雌激素缺乏的妇女的益处和降低心血管疾病风险具有重要的生物医学意义。这个 线粒体靶向抗氧化剂MitoQ可能是一种替代E2恢复AE-内皮信号转导的方法 雌激素缺乏绝经后妇女，因为它最近被证实对降低活性氧有效 物种(ROS)和氧化应激，以及改善该人群的内皮功能。因此， 这项应用的总体目标是评估为期12周的随机对照试验的疗效。 强度AE训练联合口服MitoQ(20 mg/d)与AE+口服安慰剂(PL)或不使用AE+MitoQ的比较 关于大血管(肱动脉血流介导的扩张；FMDBA)和微血管(前臂血流) 健康E_2缺乏者对臂内注射乙酰胆碱的反应 绝经后的女性。与NO生物利用度、线粒体功能、 ROS/氧化应激，以及“循环因素”的影响。我们假设 AE+MitoQ将同时改善FMDBA和FBFAch&>；AE+PL和&>No AE+MitoQ，而不是AE+MitoQ 改善FMDBA和FBFAch&GT；AE+PL。在内皮功能方面，AE+MitoQ与 AE+PL和没有AE+MitoQ，以及没有AE+MitoQ与AE+PL相比，都将得到更大的改进 在无生物利用度、线粒体功能、线粒体和全细胞ROS相关的抑制 内皮功能至少在一定程度上与“循环因子”的变化有关。由此产生的预期结果 研究将确定MitoQ对绝经后E2缺乏患者恢复AE-内皮信号的有效性 妇女，并将为制定特定性别的AE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。

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.