MitoQ protects against hyperpermeability of endothelium barrier in acute lung injury via a Nrf2-dependent mechanism.
MitoQ protects against hyperpermeability of endothelium barrier in acute lung injury via a Nrf2-dependent mechanism.
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MitoQ 通过 Nrf2 依赖性机制防止急性肺损伤中内皮屏障通透性过高
DOI：
10.1016/j.redox.2021.101936
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发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Xu F
中科院分区：
文献类型：
--
作者：
Cen M;Ouyang W;Zhang W;Yang L;Lin X;Dai M;Hu H;Tang H;Liu H;Xia J;Xu F
最近，大量证据表明，急性肺损伤（ALI）及其最严重的急性呼吸窘迫综合征（ARDS）期间，活性氧（ROS）的过量产生和线粒体破坏会加剧炎症过程。为了确定抗氧化是否可以作为这一过程中的治疗策略之一，我们选择了线粒体靶向抗氧化剂mitoQ作为ROS清除剂来研究抗氧化在ALI中的作用。mitoQ被证明可以有效减少线粒体中产生的ROS。我们证明了ALI过程中发生过氧化，这可以通过mitoQ来减少。同时，腹腔注射mitoQ可部分逆转ALI小鼠内皮细胞凋亡，伴肺血管通透性增高，肺功能受损。此外，在体外研究中，脂多糖（LPS）诱导人肺微血管内皮细胞（hpmes）产生过多的ROS，线粒体功能障碍和凋亡，并通过mitoQ纠正。为了探索其潜在的机制，我们进行了rna测序，发现mitoQ治疗组肌肉筋膜神经性纤维肉瘤F （MafF）的表达显著上调。此外，mitoQ抑制nf - e2相关因子2 （Nrf2）的降解和核易位增加，并上调其下游抗氧化反应元件（AREs），如血红素加氧酶(HO)-1和NAD(P)H：醌氧化还原酶(NQO)-1。用Nrf2或Maff siRNA转染hpmes可消除这种效应。在Nrf2缺失小鼠中，mitoQ对LPS模型ALI的保护作用基本消失。综上所述，这些结果为了解抗氧化如何通过维持线粒体止血、抑制内皮细胞凋亡、减轻内皮破坏和通过Nrf2-MafF/ARE途径调节肺部炎症对ALI产生有益影响提供了新的见解。
Recently, numerous evidence has revealed that excessive reactive oxygen species (ROS) production and mitochondrial disruption during acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS) will aggravate the inflammatory process. To identify whether antioxidation can be one of the treatment strategies during this progress, we chose mitoQ, a mitochondria-targeted antioxidant that was proved to be effective in reducing ROS generated in mitochondria, as a ROS scavenger to investigate the role of antioxidation in ALI. We demonstrated that overoxidation occurred during the process of ALI, which could be reduced by mitoQ. In the meantime, apoptosis of endothelial cells of ALI mice, accompanied by hyperpermeability of pulmonary vascular and impaired pulmonary function, was partially reversed following an intraperitoneal injection of mitoQ. Moreover, in in vitro study, lipopolysaccharides (LPS) induced excessive ROS production, mitochondrial dysfunction and apoptosis in human pulmonary microvascular endothelial cells (HPMECs), which were rectified by mitoQ. To explore underlying mechanisms, we proceeded RNA-sequencing and found significantly upregulated expression of musculoaponeurotic fibrosarcoma F (MafF) in mitoQ treated group. Additionally, mitoQ inhibited the degradation and increased nuclear translocation of NF-E2-related factor 2 (Nrf2) and upregulated its downstream antioxidant response elements (AREs), such as heme oxygenase (HO)-1 and NAD(P)H:quinone oxidoreductase (NQO)-1. This effect was abolished by transfecting HPMECs with Nrf2 or Maff siRNA. In Nrf2 deficient mice, the protective effects of mitoQ on LPS model of ALI were largely vanished. Taken together, these results provide insights into how antioxidation exerts beneficial effects on ALI via maintaining mitochondrial hemostasis, inhibiting endothelial cells apoptosis, attenuating the endothelial disruption and regulating lung inflammation via Nrf2-MafF/ARE pathway.
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影响因子：
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作者：
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DOI：
10.1073/pnas.172398899
发表时间：
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