Mitochondria-dependent apoptotic signaling has a critical role in the pathogenesis of vascular hyperpermeability (VH). Dynamin-related protein-1- (Drp-1-) mediated mitochondrial fission plays an important role in mitochondrial homeostasis. In the present study, we studied the involvement of Drp-1 in resistance to VH induced by lipopolysaccharide (LPS). To establish the model of LPS-induced VH, LPS at 15 mg/kg was injected into rats in vivo and rat pulmonary microvascular endothelial cells were exposed to 500 ng/ml LPS in vitro. We found that depletion of Drp-1 remarkedly exacerbated the mitochondria-dependent apoptosis induced by LPS, as evidenced by reduced apoptosis, mitochondrial membrane potential (MMP) depolarization, and activation of caspase-3 and caspase-9. Increased FITC-dextran flux indicated endothelial barrier disruption. In addition, overexpression of Drp-1 prevented LPS-induced endothelial hyperpermeability and upregulated mitophagy, as evidenced by the loss of mitochondrial mass and increased PINK1 expression and mitochondrial Parkin. However, the mitophagy inhibitor, 3-Methyladenine, blocked these protective effects of Drp-1. Furthermore, inhibition of Drp-1 using mitochondrial division inhibitor 1 markedly inhibited LPS-induced mitophagy and aggravated LPS-induced VH, as shown by increased FITC-dextran extravasation. These findings implied that Drp-1 strengthens resistance to mitochondria-dependent apoptosis by regulating mitophagy, suggesting Drp-1 as a possible therapeutic target in LPS-induced VH.

中文翻译：

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Drp-1作为脂多糖诱导的血管通透性的潜在治疗靶标。

线粒体依赖性凋亡信号在血管通透性（VH）的发病机理中具有关键作用。动力相关蛋白1（Drp-1-）介导的线粒体裂变在线粒体内稳态中起重要作用。在本研究中，我们研究了Drp-1参与脂多糖（LPS）诱导的VH抗性。为了建立LPS诱导的VH模型，将15 mg / kg的LPS体内注射到大鼠中，并将大鼠肺微血管内皮细胞体外暴露于500 ng / ml LPS。我们发现，Drp-1的耗竭显着加剧了LPS诱导的线粒体依赖性细胞凋亡，这可通过减少细胞凋亡，线粒体膜电位（MMP）去极化以及激活caspase-3和caspase-9来证明。FITC-葡聚糖通量增加表明内皮屏障被破坏。此外，Drp-1的过表达可防止LPS诱导的内皮通透性过高和线粒体上调，这可通过线粒体质量的丧失和PINK1表达以及线粒体Parkin的增加来证明。但是，线粒体抑制剂3-甲基腺嘌呤阻止了Drp-1的这些保护作用。此外，如FITC-葡聚糖外渗增加所示，使用线粒体分裂抑制剂1抑制Drp-1可显着抑制LPS诱导的线粒体吞噬并加剧LPS诱导的VH。