Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment.
Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment.
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DOI：
10.1093/toxsci/kft105
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发表时间：
2013-08
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影响因子：
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通讯作者：
Stephen Y. Xue;Valeria Y. Hebert;Danicia M Hayes;Corie N Robinson;Mitzi C. Glover;T. Dugas
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文献类型：
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作者：
Stephen Y. Xue;Valeria Y. Hebert;Danicia M Hayes;Corie N Robinson;Mitzi C. Glover;T. Dugas
心血管并发症已被记录在HIV-1感染人群中，抗逆转录病毒治疗可能发挥作用。核苷类逆转录酶抑制剂（NRTI）是抗逆转录病毒药物，已知可诱导内皮细胞线粒体损伤，最终导致内皮功能障碍，这是动脉粥样硬化形成的起始事件。虽然NRTI诱导的内皮细胞毒性的机制尚不清楚，但我们先前的工作表明可能涉及线粒体氧化应激。为了进一步阐明毒性机制，用不同亚类的NRTI处理内皮细胞，并评估活性氧（ROS）水平和线粒体功能。为了测试线粒体电子传递的拯救是否减弱NRTI诱导的内皮细胞毒性，在某些情况下，用电子传递辅因子辅酶Q10（Q10）共处理细胞。在4- 6 h，NRTIs增加了ROS水平，但降低了电子传递链复合物I-IV的活性、ATP水平和NAD/NADH比值。此外，一氧化氮水平降低，而内皮素-1释放增加。Q10消除NRTI诱导的线粒体损伤和对内皮激动剂产生的影响。有趣的是，在仅用NRTI处理的细胞中，线粒体毒性的标志物在18- 24小时恢复到基线水平，表明清除受损线粒体的补偿机制。使用共聚焦显微镜，分别利用自噬和线粒体自噬标记物LC-3和Nix进行确认，我们在处理后8- 10小时观察到线粒体的自噬。Q10阻止NRTI介导的LC-3增加。这些结果表明，NRTI诱导的线粒体自噬可能参与NRTI诱导的内皮功能障碍，这种损害可能是由氧化损伤。此外，补充Q10可能会预防NRTI诱导的内皮功能障碍。
Cardiovascular complications have been documented in HIV-1 infected populations, and antiretroviral therapy may play a role. Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals known to induce mitochondrial damage in endothelial cells, culminating in endothelial dysfunction, an initiating event in atherogenesis. Though the mechanism for NRTI-induced endothelial toxicity is not yet clear, our prior work suggested that a mitochondrial oxidative stress may be involved. To further delineate the mechanism of toxicity, endothelial cells were treated with NRTIs of varying subclasses, and the level of reactive oxygen species (ROS) and mitochondrial function were assessed. To test whether rescue of mitochondrial electron transport attenuated NRTI-induced endothelial cytotoxicity, in some cases, cells were cotreated with the electron transport cofactor coenzyme Q10 (Q10). At 4-6h, NRTIs increased levels of ROS but decreased the activities of electron transport chain complexes I-IV, levels of ATP and the NAD/NADH ratio. Moreover, nitric oxide levels were decreased, whereas endothelin-1 release was increased. Q10 abolished NRTI-induced mitochondria injury and effects on endothelial agonist production. Interestingly, in cells treated with NRTIs only, markers for mitochondrial toxicity returned to baseline levels by 18-24h, suggesting a compensatory mechanism for clearing damaged mitochondria. Using confocal microscopy, with confirmation utilizing the autophagy and mitophagy markers LC-3 and Nix, respectively, we observed autophagy of mitochondria at 8-10h after treatment. Q10 prevented NRTI-mediated increase in LC-3. These findings suggest that NRTI-induced mitophagy may be involved in NRTI-induced endothelial dysfunction and that this damage likely results from oxidant injury. Further, Q10 supplementation could potentially prevent NRTI-induced endothelial dysfunction.