MitoQ Supplementation for Improving Vascular Endothelial Function in Older Adults

 描述(申请人提供)：高龄是心血管疾病(CVD)的主要危险因素，主要是由于动脉的不利变化。动脉老化的一个主要特征是血管内皮功能障碍的发展，通过内皮依赖性扩张(EDD)的下降来评估。随着年龄的增长，EDD受损是由于氧化应激继发于血管扩张和血管保护分子一氧化氮(NO)的生物可利用性降低所致。与年龄相关的血管氧化应激的一个主要因素是线粒体活性氧物种(MtROS)的过度产生。因此，降低mtROS的治疗可能会改善血管内皮功能，降低中老年人(MA/O)的心血管风险。Mitoquone(MitoQ)是一种针对线粒体的抗氧化剂，与传统的外源抗氧化剂不同，它在细胞线粒体中的累积水平是细胞胞浆的100-1000倍，并减少体内mtROS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4周的MitoQ完全恢复了老年(26-28个月)小鼠的NO介导的EDD，并逆转了与年龄相关的主动脉线粒体超氧化物生产和氧化应激的增加。目前这项研究的目标是将我们的临床前发现转化为MA/O成年人。我们提出了一项随机、双盲、安慰剂对照的交叉试验研究，为口服MitoQ对改善患有基线内皮功能障碍的健康MA/O成年人(60-79岁；n=21)的NO介导的EDD的有效性提供第一个证据。为了深入了解MitoQ可能改善这一组EDD的机制，我们将使用创新的翻译技术来评估内皮细胞mtROS的产生、mtROS介导的EDD抑制以及系统和/或血管内皮细胞线粒体功能、氧化应激和炎症的标记。假设1：口服MitoQ补充剂6周会增加MA/O成人NO介导的EDD。假设2：MitoQ治疗改善EDD将通过减少内皮细胞mtROS的产生和与mtROS相关的抑制EDD，并将与减少血管内皮细胞和全身氧化应激有关。这项研究将结合临床相关的功能评估和创新的机制分析，以探索一种新的干预方法，以减少线粒体衍生的氧化应激，改善患有内皮功能障碍但没有临床疾病的MA/O成人的NO介导的EDD。

 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.