Down-regulation of miR-204 attenuates endothelial-mesenchymal transition by enhancing autophagy in hypoxia-induced pulmonary hypertension
Down-regulation of miR-204 attenuates endothelial-mesenchymal transition by enhancing autophagy in hypoxia-induced pulmonary hypertension
复制标题
miR-204的下调通过增强缺氧诱导的肺动脉高压中的自噬来减弱内皮-间质转化
DOI：
10.1016/j.ejphar.2019.172673
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发表时间：
2019-11-15
影响因子：
5
通讯作者：
Hu, Chang-Ping
中科院分区：
文献类型：
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作者：
Liu, Ting;Zou, Xiao-Zhou;Hu, Chang-Ping
肺动脉重构是肺动脉高压（PH）时肺动脉压力升高的重要原因。近年来，越来越多的证据支持内皮-间充质转化（EndMT）在肺动脉重构中的作用，但其潜在机制仍不清楚。miR-204在肺动脉平滑肌细胞（PASMCs）中具有抗增殖和促凋亡作用，与PH有关，但其在EndMT中的作用尚不清楚。本研究发现，缺氧可下调大鼠肺动脉内膜和人肺动脉内皮细胞（HPAECs）中miR-204的表达，而进一步下调miR-204抑制剂可抑制缺氧诱导的EndMT。此外，缺氧诱导的大鼠肺动脉内膜和HPAECs自噬通过p62依赖的Snail和Twist降解抑制缺氧诱导的EndMT。此外，自噬由靶向ATG 7的miR-204调节。虽然据报道PASMCs中miR-204的下调通过增加细胞增殖促进了野百合碱诱导的肺动脉高压，但我们的数据表明，内皮细胞中miR-204的下调在EndMT过程中具有重要的作用，尽管是二分法的，它通过增强自噬来减弱EndMT，从而在一定程度上改善缺氧诱导的PH。
Pulmonary arterial remodeling is a crucial cause of increased pulmonary artery pressure during pulmonary hypertension (PH). Recently, growing evidence has upheld the contribution of endothelial-mesenchymal transition (EndMT) to pulmonary arterial remodeling, but the underlying mechanisms remain largely unaddressed. miR-204 has been implicated in PH, being anti-proliferative and pro-apoptotic in pulmonary artery smooth muscles cells (PASMCs), but its role in EndMT is still unknown. Here we found that miR-204 was down-regulated by hypoxia in rat pulmonary arterial intima and human pulmonary artery endothelial cells (HPAECs), and its further down-regulation by using miR-204 inhibitor suppressed hypoxia-induced EndMT. Moreover, autophagy, evoked by hypoxia in rat pulmonary arterial intima and HPAECs, suppressed hypoxia-induced EndMT via p62-dependent degradation of Snail and Twist. Additionally, autophagy was regulated by miR-204 targeting ATG7. While down-regulation of miR-204 in PASMCs reportedly promoted monocrotaline-induced pulmonary arterial hypertension via increased cell proliferation, our data suggested an important, albeit dichotomous, role of miR-204 down-regulation in endothelial cells in the process of EndMT that it attenuated EndMT by enhancing autophagy, thereby ameliorating hypoxia-induced PH to some extent.