DJ-1 plays an obligatory role in the cardioprotection of delayed hypoxic preconditioning against hypoxia/reoxygenation-induced oxidative stress through maintaining mitochondrial complex I activity
DJ-1 plays an obligatory role in the cardioprotection of delayed hypoxic preconditioning against hypoxia/reoxygenation-induced oxidative stress through maintaining mitochondrial complex I activity
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DJ-1 通过维持线粒体复合物 I 活性，在延迟缺氧预处理对抗缺氧/复氧诱导的氧化应激的心脏保护中发挥重要作用。
DOI：
10.1002/cbf.3326
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发表时间：
2018-04-01
影响因子：
3.6
通讯作者：
Chen, He-Ping
中科院分区：
文献类型：
--
作者：
Ding, Hao;Xu, Xing-Wang;Chen, He-Ping
最近有报道称 DJ-1 通过抑制缺氧/复氧 (H/R) 诱导的氧化应激来介导延迟缺氧预适应 (DHP) 的心脏保护作用，但其对抗 DHP 期间 H/R 诱导的氧化应激的机制尚未完全阐明。在这里，使用完善的 DHP 细胞模型，我们再次发现 DHP 显着提高了细胞活力并减少了乳酸脱氢酶的释放，同时上调了经 H/R 处理的 H9c2 细胞中的 DJ-1 蛋白表达。重要的是，DHP 有效地提高了 H/R 后线粒体复合物 I 的活性，并减弱了 H/R 诱导的线粒体活性氧 (ROS) 的产生和随后的氧化应激，与 H/R 组相比，还原型谷胱甘肽/氧化型谷胱甘肽比率的下降幅度要小得多，细胞内 ROS 和丙二醛含量的增加要小得多，这证明了这一点。然而，DHP 的上述作用被短发夹 RNA 的 DJ-1 敲低所拮抗，但被 DJ-1 过表达所模拟。有趣的是，鱼藤酮对线粒体复合物 I 的药理学抑制减弱了 DHP 和 DJ-1 过度表达引起的所有保护作用，包括维持线粒体复合物 I 以及抑制线粒体 ROS 生成和随后的氧化应激。总而言之，这项工作揭示了保持线粒体复合物 I 活性并随后抑制线粒体 ROS 生成可能是 DJ-1 介导 DHP 对抗 H/R 诱导的氧化应激损伤的心脏保护作用的新机制。
DJ-1 was recently reported to mediate the cardioprotection of delayed hypoxic preconditioning (DHP) by suppressing hypoxia/reoxygenation (H/R)-induced oxidative stress, but its mechanism against H/R-induced oxidative stress during DHP is not fully elucidated. Here, using the well-established cellular model of DHP, we again found that DHP significantly improved cell viability and reduced lactate dehydrogenase release with concurrently up-regulated DJ-1 protein expression in H9c2 cells subjected to H/R. Importantly, DHP efficiently improved mitochondrial complex I activity following H/R and attenuated H/R-induced mitochondrial reactive oxygen species (ROS) generation and subsequent oxidative stress, as demonstrated by a much smaller decrease in reduced glutathione/oxidized glutathione ratio and a much smaller increase in intracellular ROS and malondialdehyde contents than that observed for the H/R group. However, the aforementioned effects of DHP were antagonized by DJ-1 knockdown with short hairpin RNA but mimicked by DJ-1 overexpression. Intriguingly, pharmacological inhibition of mitochondria complex I with Rotenone attenuated all the protective effects caused by DHP and DJ-1 overexpression, including maintenance of mitochondria complex I and suppression of mitochondrial ROS generation and subsequent oxidative stress. Taken together, this work revealed that preserving mitochondrial complex I activity and subsequently inhibiting mitochondrial ROS generation could be a novel mechanism by which DJ-1 mediates the cardioprotection of DHP against H/R-induced oxidative stress damage.