Chronic mitochondria antioxidant treatment in older adults alters the circulating milieu to improve endothelial cell function and mitochondrial oxidative stress.
Chronic mitochondria antioxidant treatment in older adults alters the circulating milieu to improve endothelial cell function and mitochondrial oxidative stress.
复制标题
老年人的慢性线粒体抗氧化治疗可改变循环环境，以改善内皮细胞功能和线粒体氧化应激。
DOI：
10.1152/ajpheart.00270.2023
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Rossman,MatthewJ
中科院分区：
文献类型：
--
作者：
Murray,KevinO;Ludwig,KatelynR;Darvish,Sanna;Coppock,McKinleyE;Seals,DouglasR;Rossman,MatthewJ
线粒体（mtROS）产生过多的活性氧是年龄相关的血管内皮功能障碍的关键因素。我们最近在一项交叉设计、安慰剂对照的老年人临床试验中显示，6周的靶向抗氧化剂（MitoQ）治疗通过降低mtROS改善了内皮功能（通过一氧化氮（NO）介导的内皮依赖性舒张（EDD）测量），并与氧化低密度脂蛋白（oxLDL）的循环水平降低相关。在此，我们使用临床试验的血浆样本进行了辅助分析，以确定MitoQ治疗介导的“循环环境”（血浆）变化是否有助于改善内皮功能及其相关机制。使用内皮功能的离体模型，在暴露于19名老年人（67 ± 1岁; 11名女性）慢性MitoQ和安慰剂补充后收集的血浆的人主动脉内皮细胞（HAEC）中定量乙酰胆碱刺激的NO产生。我们还评估了血浆对内皮细胞（EC）mtROS生物活性的影响以及血浆介导的变化中较低循环oxLDL的作用。与安慰剂相比，在暴露于MitoQ治疗后从受试者收集的血浆的HAEC中，NO产生高出25%（P = 0.0002），mtROS生物活性低出25%（P= 0.003）。离体NO产生和体内NO介导的EDD的改善与MitoQ相关（r= 0.4683;P= 0.0431）。将MitoQ后收集的血浆中的oxLDL增加至安慰剂水平可消除MitoQ处理对NO产生和mtROS生物活性的影响，而抑制内源性oxLDL与其凝集素样氧化低密度脂蛋白受体1（LOX-1）的结合可防止这些影响。这些发现为MitoQ治疗改善老年人血管内皮功能的机制提供了新的见解。新&值得注意的是，长期补充一种靶向抗氧化剂（MitoQ）可以改善老年人的血管内皮功能，但其作用机制尚不完全清楚。在这里，我们表明，MitoQ补充剂导致循环环境（血浆）的变化，包括氧化低密度脂蛋白的减少，从而增强一氧化氮的产生并减少内皮细胞中的线粒体氧化应激。这些发现提供了关于MitoQ改善年龄相关内皮功能障碍的机制的新信息。
Excessive reactive oxygen species production by mitochondria (mtROS) is a key contributor to age-related vascular endothelial dysfunction. We recently showed in a crossover design, placebo-controlled clinical trial in older adults that 6 wk of treatment with the mitochondria-targeted antioxidant (MitoQ) improved endothelial function, as measured by nitric oxide (NO)-mediated endothelium-dependent dilation (EDD), by lowering mtROS and was associated with reduced circulating levels of oxidized low-density lipoprotein (oxLDL). Here, we conducted an ancillary analysis using plasma samples from our clinical trial to determine if MitoQ treatment-mediated changes in the “circulating milieu” (plasma) contribute to improvements in endothelial function and the mechanisms involved. With the use of an ex vivo model of endothelial function, acetylcholine-stimulated NO production was quantified in human aortic endothelial cells (HAECs) exposed to plasma collected after chronic MitoQ and placebo supplementation in 19 older adults (67 ± 1 yr; 11 females). We also assessed the influence of plasma on endothelial cell (EC) mtROS bioactivity and the role of lower circulating oxLDL in plasma-mediated changes. NO production was ∼25% higher (P= 0.0002) and mtROS bioactivity was ∼25% lower (P= 0.003) in HAECs exposed to plasma collected from subjects after MitoQ treatment versus placebo. Improvements in NO production ex vivo and NO-mediated EDD in vivo with MitoQ were correlated (r= 0.4683;P= 0.0431). Increasing oxLDL in plasma collected after MitoQ to placebo levels abolished MitoQ treatment effects on NO production and mtROS bioactivity, whereas inhibition of endogenous oxLDL binding to its lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) prevented these effects. These findings provide novel insight into the mechanisms by which MitoQ treatment improves endothelial function in older adults.NEW & NOTEWORTHYChronic supplementation with a mitochondria-targeted antioxidant (MitoQ) improves vascular endothelial function in older adults, but the mechanisms of action are incompletely understood. Here, we show that MitoQ supplementation leads to changes in the circulating milieu (plasma), including reductions in oxidized low-density lipoprotein that enhance nitric oxide production and reduce mitochondrial oxidative stress in endothelial cells. These findings provide new information regarding the mechanisms by which MitoQ improves age-related endothelial dysfunction.
DOI：
10.1152/ajpheart.00015.2005
发表时间：
2005-08-01
影响因子：
4.8
作者：
Zmijewski, JW;Moellering, DR;Darley-Usmar, VM
通讯作者：
Darley-Usmar, VM
DOI：
10.1016/j.vascn.2005.06.004
发表时间：
2005-11-01
影响因子：
1.9
作者：
Lacza, Zsombor;Horvath, Eszter M.;Busija, David W.
通讯作者：
Busija, David W.
DOI：
10.1111/j.1440-1681.2004.04022.x
发表时间：
2004-07-01
影响因子：
2.9
作者：
Imanishi, T;Hano, T;Nishio, I
通讯作者：
Nishio, I