Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus.
Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus.
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DOI：
10.1161/circulationaha.110.014506
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发表时间：
2011-07-26
期刊：
影响因子：
37.8
通讯作者：
Vita JA
中科院分区：
文献类型：
--
作者：
Shenouda SM;Widlansky ME;Chen K;Xu G;Holbrook M;Tabit CE;Hamburg NM;Frame AA;Caiano TL;Kluge MA;Duess MA;Levit A;Kim B;Hartman ML;Joseph L;Shirihai OS;Vita JA
内皮功能障碍促进糖尿病患者动脉粥样硬化的发展，但在这种情况下内皮功能障碍的机制尚未完全明确。近期研究表明，糖尿病患者的线粒体动力学发生改变，线粒体分裂增加且活性氧（ROS）产生增多。我们研究了动力学改变对糖尿病内皮功能障碍的影响。
我们观察到，与健康对照组（n = 9）相比，从糖尿病患者（n = 10）新鲜分离的静脉内皮细胞中线粒体碎片化（P = 0.002）且分裂蛋白1（Fis1）表达增加（P < 0.0001）。在暴露于30 mM葡萄糖的培养人主动脉内皮细胞中，我们观察到类似的线粒体网络缺失以及Fis1和动力相关蛋白1（Drp1，线粒体分裂所需的蛋白质）表达增加。线粒体动力学改变与线粒体ROS产生增加以及激动剂刺激的内皮型一氧化氮合酶（eNOS）激活和环磷酸鸟苷（cGMP）产生显著受损相关。用小干扰RNA（siRNA）沉默Fis1或Drp1表达可减弱高糖诱导的线粒体网络、ROS产生、eNOS激活和cGMP产生的改变。一种细胞内ROS清除剂没有额外的益处，这表明线粒体分裂增加可能通过ROS增加损害内皮功能。
这些发现表明线粒体分裂增加是糖尿病状态下内皮功能障碍的一个促成机制。
Endothelial dysfunction contributes to the development of atherosclerosis in patients with diabetes mellitus, but the mechanisms of endothelial dysfunction in this setting are incompletely understood. Recent studies have shown altered mitochondrial dynamics in diabetes mellitus with increased mitochondrial fission and production of reactive oxygen species (ROS). We investigated the contribution of altered dynamics to endothelial dysfunction in diabetes. We observed mitochondrial fragmentation (P=0.002) and increased expression of fission-1 protein (Fis1, P<0.0001) in venous endothelial cells freshly isolated from patients with diabetes mellitus (n=10) compared to healthy controls (n=9). In cultured human aortic endothelial cells exposed to 30 mM glucose, we observed a similar loss of mitochondrial networks and increased expression of Fis1 and dynamin-related protein-1 (Drp1), proteins required for mitochondrial fission. Altered mitochondrial dynamics was associated with increased mitochondrial ROS production and a marked impairment of agonist-stimulated activation of endothelial nitric oxide synthase (eNOS) and cGMP production. Silencing Fis1 or DRP1 expression with siRNA blunted high glucose-induced alterations in mitochondrial networks, ROS production, eNOS activation, and cGMP production. An intracellular ROS scavenger provided no additional benefit, suggesting that increased mitochondrial fission may impair endothelial function via increased ROS. These findings implicate increased mitochondrial fission as a contributing mechanism for endothelial dysfunction in diabetic states.