Mdivi-1 attenuates oxidative stress and exerts vascular protection in ischemic/hypoxic injury by a mechanism independent of Drp1 GTPase activity
Mdivi-1 attenuates oxidative stress and exerts vascular protection in ischemic/hypoxic injury by a mechanism independent of Drp1 GTPase activity
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Mdivi-1 通过独立于 Drp1 GTPase 活性的机制减轻氧化应激并在缺血/缺氧损伤中发挥血管保护作用
DOI：
10.1016/j.redox.2020.101706
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发表时间：
2020-10-01
期刊：
影响因子：
11.4
通讯作者：
Li, Tao
中科院分区：
文献类型：
--
作者：
Duan, Chenyang;Wang, Li;Li, Tao
缺血/缺氧性损伤后的血管功能障碍如血管低反应性是受伤患者死亡的主要原因。在这项研究中，我们发现，线粒体分裂抑制剂1（Mdivi-1），动力蛋白相关蛋白1（Drp 1）的选择性抑制剂治疗，通过减轻氧化应激显着改善缺血大鼠的血管反应性。Mdivi-1的抗氧化作用是相对Drp 1独立的，可能是由于抗氧化酶，SOD 1和过氧化氢酶的水平增加，以及增强Nrf 2的表达。此外，我们发现，虽然Mdivi-1在血管平滑肌细胞中对Drp 1 GTdR活性几乎没有影响，但它抑制了缺氧诱导的Drp 1 Ser-616磷酸化，减少了过度的线粒体分裂并略微增强了线粒体融合。这些作用可能有助于在缺血/缺氧损伤的早期阶段的血管保护。最后，Mdivi-1稳定了血流动力学，增加了重要器官灌注，并改善了缺血/缺氧损伤后大鼠的存活率，证明了缺血/缺氧损伤的有希望的治疗剂。
Vascular dysfunctions such as vascular hyporeactivity following ischemic/hypoxic injury are a major cause of death in injured patients. In this study, we showed that treatment with mitochondrial division inhibitor 1 (Mdivi-1), a selective inhibitor of dynamin-related protein 1 (Drp1), significantly improved vascular reactivity in ischemic rats by attenuating oxidative stress. The antioxidative effects of Mdivi-1 were relatively Drp1 - independent, and possibly due to an increase in the levels of the antioxidant enzymes, SOD1 and catalase, as well as to enhanced Nrf2 expression. In addition, we found that while Mdivi-1 had little effect on Drp1 GTPase activity in vascular smooth muscle cells, it inhibited hypoxia-induced Drp1 phosphorylation at Ser-616, reducing excessive mitochondrial fission and slightly enhancing mitochondrial fusion. These effects possibly contributed to vascular protection at an early stage of ischemic/hypoxic injury. Finally, Mdivi-1 stabilized hemodynamics, increased vital organ perfusion, and improved rat survival after ischemic/hypoxic injury, proving a promising therapeutic agent for ischemic/hypoxic injury.