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

项目总结/摘要 内皮功能障碍是年龄相关性心血管疾病（CVD）病因学中的一个关键因素， 绝经后妇女的主要死因。有规律的有氧运动（AE）可以增强宏观和 通过减少氧化应激和保护一氧化氮（NO）来改善老年男性的微血管内皮功能 然而，在雌激素（E2）缺乏的患者中，类似的AE训练改善减少或不存在。 绝经后妇女。AE训练改善NO介导的内皮功能和氧化应激 在绝经后妇女中，E2治疗，表明E2在内皮适应AE中的重要作用 在女人身上。E2的临床使用禁忌用于此目的，因此建立了替代药理学 可以作为E2到EAE信号传导的替代品来管理血管内皮细胞的方法， 在E2缺乏的绝经后妇女中，减少心血管疾病风险的益处在生物医学上是重要的。的 血管靶向抗氧化剂MitoQ可能是E2的替代品，用于恢复AE-内皮细胞信号传导， E2缺乏的绝经后妇女考虑到其最近确定的减少活性氧的有效性 物种（ROS）和氧化应激，并改善该群体中的内皮功能。因此 本申请的总体目的是评估一项为期12周的中度 与AE+口服安慰剂（PL）或无AE+MitoQ相比，强度AE训练联合口服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 肱动脉内输注乙酰胆碱的反应（FBFAch） 绝经后妇女。与NO生物利用度，线粒体功能， ROS/氧化应激，以及“循环因子”的影响也将被获得。我们假设 AE+MitoQ将改善FMDBA和FBFAch > AE+PL和>无AE+MitoQ，并且无AE+MitoQ将改善FMDBA和FBFAch。 改善FMDBA和FBFAch > AE+PL。AE+MitoQ与MitoQ相比， AE+PL和无AE+MitoQ，以及无AE+MitoQ与AE+PL相比，将通过更大的改善介导 在NO生物利用度、线粒体功能以及线粒体和全细胞ROS相关抑制中， 内皮功能至少部分与“循环因子”的变化有关。预期的结果 研究将确定MitoQ在E2缺乏的绝经后患者中恢复AE-内皮信号传导的疗效 女性，并将为制定性别特异性AE的循证指南提供基础 改善绝经后妇女的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.