MitoQ Supplementation for Improving Vascular Endothelial Function in Older Adults

 描述（由申请人提供）：年龄增长是心血管疾病（CVD）的主要风险因素，主要是由于动脉的不良变化。动脉老化的一个主要特征是血管内皮功能障碍的发展，如通过内皮依赖性舒张（EDD）的下降所评估的。随着年龄的增长，EDD受损是由血管舒张和血管保护分子一氧化氮（NO）的生物利用度降低引起的，继发于氧化应激。与年龄相关的血管氧化应激的一个主要贡献者是线粒体活性氧（mtROS）的过度产生。因此，减少mtROS的治疗可能会改善血管内皮功能，降低中老年（MA/O）成人的CVD风险。线粒体醌（MitoQ）是一种靶向抗氧化剂，与传统的外源性抗氧化剂相比，其在细胞线粒体中的积累水平比细胞质高100- 1，000倍，并降低体内线粒体ROS介导的氧化应激。我们实验室的临床前研究结果表明，在饮用水中补充MitoQ 4周完全恢复了老年（26-28月龄）小鼠中NO介导的EDD，并逆转了主动脉线粒体超氧化物生成和氧化应激的年龄相关性增加。目前研究的目标是将我们的临床前研究结果转化为MA/O成人。我们提出了一项随机、双盲、安慰剂对照的交叉初步研究，以提供口服MitoQ补充剂改善基线内皮功能障碍的健康MA/O成人（60-79岁; n=21）NO介导的EDD的疗效的第一个证据。为了深入了解MitoQ可能改善该组EDD的机制，我们将采用创新的翻译技术来评估内皮细胞mtROS的产生，mtROS介导的EDD抑制，以及线粒体功能，氧化应激和炎症的全身和/或血管内皮细胞标志物。假设1：6周的口服MitoQ补充将增加MA/O成人中NO介导的EDD。假设二：MitoQ治疗改善EDD将通过减少内皮细胞mtROS产生和mtROS相关的EDD抑制介导，并将与血管内皮和全身氧化应激降低相关。本研究将结合联合收割机临床相关的功能评估与创新的机制分析，以研究一种新的干预方法，用于减少血管内皮源性氧化应激和改善血管内皮功能障碍的MA/O成人中NO介导的EDD，但无临床疾病。

 DESCRIPTION (provided by applicant): Advancing age is the primary risk factor for cardiovascular diseases (CVD) due largely to adverse changes to arteries. A major feature of arterial aging is the development of vascular endothelial dysfunction as assessed by a decline in endothelium-dependent dilation (EDD). Impaired EDD with advancing age is caused by reduced bioavailability of the vasodilatory and vascular protective molecule nitric oxide (NO), secondary to oxidative stress. A major contributor to age-associated vascular oxidative stress is excessive production of mitochondrial reactive oxygen species (mtROS). As such, therapies that reduce mtROS may improve vascular endothelial function and decrease CVD risk in middle-aged/older (MA/O) adults. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant that, in contrast to traditional exogenous antioxidants, accumulates at levels 100-1,000-fold higher in the mitochondria vs. cytosol of cells, and reduces mtROS-mediated oxidative stress in vivo. Preclinical findings from our lab indicate that 4 weeks of MitoQ supplementation in the drinking water completely restores NO-mediated EDD in old (26-28 mo) mice, and reverses the age-related increases in aortic mitochondrial superoxide production and oxidative stress. The goal of the current study is to translate our preclinical findings to MA/O adults. We propose a randomized, double-blind, placebo-controlled cross-over pilot study to provide the first evidence for the efficacy of oral MitoQ supplementation to improve NO-mediated EDD in healthy MA/O adults (60-79 yr; n=21) with baseline endothelial dysfunction. To gain insight into the mechanisms by which MitoQ may improve EDD in this group, we will employ innovative translational techniques to assess endothelial cell mtROS production, mtROS-mediated suppression of EDD, and systemic and/or vascular endothelial cell markers of mitochondrial function, oxidative stress, and inflammation. Hypothesis 1: 6 weeks of oral MitoQ supplementation will increase NO-mediated EDD in MA/O adults. Hypothesis 2: Improved EDD with MitoQ treatment will be mediated by reduced endothelial cell mtROS production and mtROS-related suppression of EDD, and will be associated with decreased vascular endothelial and systemic oxidative stress. This investigation will combine clinically relevant functional assessments with innovative mechanistic analyses to investigate a novel intervention approach for reducing mitochondria-derived oxidative stress and improving NO-mediated EDD in MA/O adults with endothelial dysfunction, but free of clinical disease.