Reactive oxygen species effect PASMCs apoptosis via regulation of dynamin-related protein 1 in hypoxic pulmonary hypertension.
Reactive oxygen species effect PASMCs apoptosis via regulation of dynamin-related protein 1 in hypoxic pulmonary hypertension.
复制标题
在缺氧性肺动脉高压中，活性氧通过调节动力相关蛋白 1 影响 PASMC 凋亡。
DOI：
10.1007/s00418-016-1424-9
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发表时间：
2016
影响因子：
2.3
通讯作者：
Zhu Daling
中科院分区：
文献类型：
--
作者：
Zhang Lixin;Ma Cui;Zhang Chen;Ma Mingfei;Zhang Fengying;Zhang Linlin;Chen Yingli;Cao Fangyuan;Li Shuzhen;Zhu Daling
在啮齿动物肺动脉高压模型中检测到高水平的活性氧和线粒体分裂蛋白动力蛋白相关蛋白1的上调，这两者都参与了肺动脉平滑肌细胞（PASMCs）的凋亡。然而，ROS和DRP 1之间的调节机制知之甚少。本研究采用ROS抑制剂、缺氧性大鼠PAH模型、小干扰RNA、聚合酶链反应、Western blot、流式细胞术、免疫组化和免疫荧光等方法。我们确定，主要来自线粒体的ROS介导PASMCs的线粒体分裂，从而促进肺血管重构。同时，我们还观察到缺氧诱导的DRP 1表达依赖于ROS的产生，尤其是线粒体ROS（mROS）的产生。此外，由缺氧引起的ROS和mROS的水平由DRP 1调节。此外，我们验证了缺氧条件下PASMCs的凋亡抑制是由于ROS/mROS和DRP 1之间的相互作用。我们的研究揭示了低氧诱导肺血管重构的新机制，提出了一种新的治疗策略，即针对ROS/mROS-DRP 1的正反馈治疗PAH。
The high level of reactive oxygen species and up-regulation of mitochondrial fission protein dynamin-related protein-1, both of which involved in pulmonary artery smooth muscle cells (PASMCs) apoptosis, have been detected in the lungs of rodent pulmonary arterial hypertension models. However, the regulatory mechanisms between ROS and DRP1 are poorly understood. In this study, ROS inhibitor, hypoxic rodent PAH models, small interfering RNA, polymerase chain reaction, Western blot, flow cytometry, immunohistochemistry and immunofluorescence were used. We determined that ROS, mainly derive from mitochondria, mediate mitochondria fission of PASMCs contributing to pulmonary vascular remodeling. Meanwhile, we also observed that hypoxia-induced DRP1 expression depends on ROS generation, especially mitochondrial ROS (mROS). Moreover, the levels of ROS and mROS evoked by hypoxia were regulated by DRP1. Furthermore, we verified the apoptosis suppression of PASMCs under hypoxia due to the interaction between ROS/mROS and DRP1. Our study reveals a novel mechanism of hypoxia-induced pulmonary vascular remodeling, suggesting a new therapeutic strategy which is targeting on the positive feedback of ROS/mROS-DRP1 for the treatment of PAH.