N-n-Butyl Haloperidol Iodide Ameliorates Oxidative Stress in Mitochondria Induced by Hypoxia/Reoxygenation through the Mitochondrial c-Jun N-Terminal Kinase/Sab/Src/Reactive Oxygen Species Pathway in H9c2 Cells
N-n-Butyl Haloperidol Iodide Ameliorates Oxidative Stress in Mitochondria Induced by Hypoxia/Reoxygenation through the Mitochondrial c-Jun N-Terminal Kinase/Sab/Src/Reactive Oxygen Species Pathway in H9c2 Cells
复制标题
N-正丁基氟哌啶醇碘化物可改善 H9c2 细胞中通过线粒体 c-Jun N 末端激酶/Sab/Src/活性氧途径缺氧/复氧诱导的线粒体氧化应激
DOI：
10.1155/2019/7417561
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发表时间：
2019-01-01
影响因子：
--
通讯作者：
Shi, Ganggang
中科院分区：
文献类型：
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作者：
Chu, Qianwen;Zhang, Yanmei;Shi, Ganggang
c-Jun N 末端激酶 (JNK) 和活性氧 (ROS) 在心肌缺血/再灌注 (I/R) 损伤中发挥重要作用。我们之前的研究表明，N-正丁基氟哌啶醇碘化物 (F2) 通过减少 I/R 引起的 ROS 产生和 JNK 激活来发挥心脏保护作用。在本研究中，我们假设H9c2细胞缺氧/复氧（H/R）后线粒体中存在JNK/Sab/Src/ROS通路，诱导线粒体氧化应激，并且F2通过调节该通路在H/R损伤期间发挥线粒体保护作用。结果表明，H/R 一方面诱导细胞质中较高水平的 ROS，另一方面通过与 Sab 共定位来激活 JNK 并易位至线粒体。此外，H/R 导致线粒体 Src 去磷酸化，随后导致氧化应激，表现为线粒体膜中 ROS 生成和氧化心磷脂的增加以及线粒体超氧化物歧化酶活性和膜电位的降低。此外，用 JNK 抑制剂或 Sab 小干扰 RNA 治疗可抑制 p-JNK 的线粒体易位，减少 p-JNK 和 Sab 在线粒体上的共定位，并减少 H/R 期间的 Src 去磷酸化和线粒体氧化应激。此外，抑制剂 PP2 使 Src 去磷酸化增加了线粒体 ROS 的产生。 F2与JNK/Sab/Src/ROS途径的抑制剂一样，下调H/R诱导的p-JNK线粒体易位以及p-JNK和Sab在线粒体上的共定位，增加Src磷酸化，并减轻上述线粒体氧化应激。总之，F2可以通过线粒体JNK/Sab/Src/ROS途径改善H9c2细胞线粒体中H/R相关的氧化应激。
Both c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS) play important roles in myocardial ischemia/reperfusion (I/R) injury. Our previous studies suggest that N-n-butyl haloperidol iodide (F2) exerts cardioprotection by reducing ROS production and JNK activation caused by I/R. In this study, we hypothesized that there is a JNK/Sab/Src/ROS pathway in the mitochondria in H9c2 cells following hypoxia/reoxygenation (H/R) that induces oxidative stress in the mitochondria and that F2 exerts mitochondrial protective effects during H/R injury by modulating this pathway. The results showed that H/R induced higher-level ROS in the cytoplasm on the one hand and JNK activation and translocation to the mitochondria by colocalization with Sab on the other. Moreover, H/R resulted in mitochondrial Src dephosphorylation, and subsequently, oxidative stress evidenced by the increase in ROS generation and oxidized cardiolipin in the mitochondrial membranes and by the decrease in mitochondrial superoxide dismutase activity and membrane potential. Furthermore, treatment with a JNK inhibitor or Sab small interfering RNA inhibited the mitochondrial translocation of p-JNK, decreased colocalization of p-JNK and Sab on the mitochondria, and reduced Src dephosphorylation and mitochondrial oxidative stress during H/R. In addition, Src dephosphorylation by inhibitor PP2 increased mitochondrial ROS production. F2, like inhibitors of the JNK/Sab/Src/ROS pathway, downregulated the H/R-induced mitochondrial translocation of p-JNK and the colocalization of p-JNK and Sab on the mitochondria, increased Src phosphorylation, and alleviated the above-mentioned mitochondrial oxidative stress. In conclusion, F2 could ameliorate H/R-associated oxidative stress in mitochondria in H9c2 cells through the mitochondrial JNK/Sab/Src/ROS pathway.