Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells
Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells
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DOI：
10.1161/01.res.86.9.960
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发表时间：
2000-05-12
影响因子：
20.1
通讯作者：
Runge, MS
中科院分区：
文献类型：
--
作者：
Ballinger, SW;Patterson, C;Runge, MS
反应性物质（reactive species，RS）参与动脉粥样硬化形成的机制尚不完全清楚。本研究旨在验证在体外血管环境中产生的RS引起线粒体损伤和功能障碍，从而可能参与动脉粥样硬化形成的起始事件的假设。在血管细胞暴露于超氧化物，过氧化氢，一氧化氮和过氧亚硝酸盐的DNA损伤进行了评估。在血管内皮细胞和平滑肌细胞中，线粒体DNA（mtDNA）相对于转录失活的核β-珠蛋白基因优先受损。同样，剂量依赖性减少mtDNA编码的mRNA转录与RS治疗。线粒体蛋白质合成也受到抑制，在剂量依赖性的方式由ONOO-，导致细胞ATP水平和线粒体氧化还原功能下降。总的来说，内皮细胞比平滑肌细胞对RS介导的损伤更敏感。总之，这些数据链接RS介导的线粒体DNA损伤，改变基因表达，线粒体功能障碍的细胞培养，并揭示RS如何可能介导血管细胞功能障碍的动脉粥样硬化的设置。
The mechanisms by which reactive species (RS) participate in the development of atherosclerosis remain incompletely understood, The present study was designed to test the hypothesis that RS produced in the vascular environment cause mitochondrial damage and dysfunction in vitro and, thus, may contribute to the initiating events of atherogenesis. DNA damage was assessed in vascular cells exposed to superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite. In both vascular endothelial and smooth muscle cells, the mitochondrial DNA (mtDNA) was preferentially damaged relative to the transcriptionally inactive nuclear beta-globin gene. Similarly, a dose-dependent decrease in mtDNA-encoded mRNA transcripts was associated with RS treatment. Mitochondrial protein synthesis was also inhibited in a dose-dependent manner by ONOO-, resulting in decreased cellular ATP levels and mitochondrial redox function. Overall, endothelial cells were more sensitive to RS-mediated damage than were smooth muscle cells. Together, these data link RS-mediated mtDNA damage, altered gene expression, and mitochondrial dysfunction in cell culture and reveal how RS may mediate vascular cell dysfunction in the setting of atherogenesis.