Propofol-induced MiR-20b expression initiates endogenous cellular signal changes mitigating hypoxia/re-oxygenation-induced endothelial autophagy in vitro
Propofol-induced MiR-20b expression initiates endogenous cellular signal changes mitigating hypoxia/re-oxygenation-induced endothelial autophagy in vitro
复制标题
丙泊酚诱导的 MiR-20b 表达启动内源性细胞信号变化，减轻体外缺氧/复氧诱导的内皮自噬。
DOI：
10.1038/s41419-020-02828-9
复制
发表时间：
2020-08-13
影响因子：
9
通讯作者：
Zhang, Liangqing
中科院分区：
文献类型：
--
作者：
Lu, Yue;Wang, Sijie;Zhang, Liangqing
某些miRNAs可以减弱缺氧/复氧诱导的自噬性细胞死亡，但这些miRNAs如何调节自噬相关的细胞信号通路，防止细胞死亡在很大程度上是未知的。在本研究中，自噬相关的miRNAs的hsa-miR-20 b进行了研究，在体外模型的缺氧/复氧诱导的内皮细胞自噬细胞死亡。其中，miR-20 b是最重要的一种miRNA，它靶向自噬激酶ULK 1，通过降低自噬体和LC 3 I向II的转化率以及P62降解，抑制缺氧/复氧损伤诱导的自噬。这些过程通过miR-20 b抑制剂的转染而逆转。ULK 1的再表达恢复了miR-20 b抑制的自噬。丙泊酚是一种常用的麻醉剂，可促进miR-20 b和胃L3的表达，并减弱内皮细胞自噬性细胞死亡。抑制内源性miR-20 b的表达或沉默胃L3减弱了丙泊酚的保护作用并加剧了自噬。此外，胃L3敲低显著抑制miR-20 b表达，但上调pri-miR-20 b表达。总之，我们的数据表明，丙泊酚可防止缺氧/复氧损伤诱导的内皮自噬细胞死亡，这与胃L3/miR-20 b/ULK 1细胞信号传导的激活有关。
Certain miRNAs can attenuate hypoxia/re-oxygenation-induced autophagic cell death reported in our previous studies, but how these miRNAs regulate the autophagy-related cellular signaling pathway in preventing cell death is largely unknown. In the current study, the autophagy-related miRNAs of hsa-miR-20b were investigated in an in vitro model of hypoxia/re-oxygenation-induced endothelial autophagic cell death. Of these, miR-20b was found to be the most important miRNA which targeted on the key autophagy kinase ULK1 and inhibited hypoxia/re-oxygenation injury-induced autophagy by decreasing both autophagosomes and LC3I to II transition rate and P62 degradation. These processes were reversed by the transfection of an miR-20b inhibitor. Re-expression of ULK1 restores miR-20b-inhibited autophagy. Propofol, a commonly used anesthetic, promoted miR-20b and METTL3 expression and attenuated endothelial autophagic cell death. The inhibited endogenous expression of miR-20b or silenced METTL3 diminished the protective effect of propofol and accentuated autophagy. Additionally, METTL3 knockdown significantly inhibited miR-20b expression but up-regulated pri-miR-20b expression. Together, our data shows that propofol protects against endothelial autophagic cell death induced by hypoxia/re-oxygenation injury, associated with activation of METTL3/miR-20b/ULK1 cellular signaling.