miR-27a promotes endothelial-mesenchymal transition in hypoxia-induced pulmonary arterial hypertension by suppressing BMP signaling
miR-27a promotes endothelial-mesenchymal transition in hypoxia-induced pulmonary arterial hypertension by suppressing BMP signaling
复制标题
miR-27a通过抑制BMP信号传导促进缺氧诱导的肺动脉高压的内皮间质转化
DOI：
10.1016/j.lfs.2019.04.038
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发表时间：
2019-06-15
期刊：
影响因子：
6.1
通讯作者：
Hu, Chang-Ping
中科院分区：
文献类型：
--
作者：
Liu, Ting;Zou, Xiao-Zhou;Hu, Chang-Ping
目的：越来越多的证据表明，内皮-间充质转化（EndMT）在肺动脉高压（PAH）时肺动脉重构中起关键作用，但其机制尚未完全阐明。miR-27 a已被证明在PAH期间促进肺动脉细胞增殖，但其在EndMT中的作用尚未探索。本研究旨在探讨miR-27 a在肺动脉高压（PAH）过程中EndMT的作用及其机制。主要方法：大鼠缺氧（10%O-2）3周诱导PAH，人肺动脉内皮细胞（HPAECs）缺氧（1%O-2）48 h诱导EndMT。采用免疫组化、原位杂交、免疫荧光、实时荧光定量PCR和Western blot检测mRNA和蛋白的表达，并采用荧光素酶法验证miR-27 a的结合位点。结果：低氧可上调大鼠肺动脉和HPAEC图尼卡内膜中miR-27 a的表达，抑制miR-27 a可抑制低氧诱导的EndMT。此外，miR-27 a的表达升高通过靶向Smad 5抑制骨形态发生蛋白（BMP）信号传导，从而减轻Id 2介导的对EndMT的2种关键介质（Snail和Twist）的抑制。因此，靶向miR-27 a相关通路可用于治疗PAH。
Aim: Growing evidence suggests that endothelial-mesenchymal transition (EndMT) play key roles in pulmonary arterial remodeling during pulmonary arterial hypertension (PAH), but the underlying mechanisms have yet to be fully understood. miR-27a has been shown to promote proliferation of pulmonary arterial cells during PAH, but its role in EndMT remains unexplored. This study was designed to investigate the role and underlying mechanism of miR-27a in EndMT during PAH.Main methods: Rats were exposed in hypoxia (10% O-2) for 3 weeks to induce PAH, and human pulmonary artery endothelial cells (HPAECs) were exposed in hypoxia (1% O-2) for 48 h to induce EndMT. Immunohistochemistry, in situ hybridization, immunofluorescence, real-time PCR and Western blot were conducted to detect the expressions of RNAs and proteins, and luciferase assay was used to verify the putative binding site of miR-27a.Key findings: We found that hypoxia up-regulated miR-27a in the tunica intima of rat pulmonary arteries and HPAECs, and that inhibition of miR-27a suppressed hypoxia-induced EndMT. Furthermore, elevated expression of miR-27a suppressed bone morphogenetic protein (BMP) signaling by targeting Smad5, thereby lessening Id2-mediated repression of the 2 critical mediators of EndMT (Snail and Twist).Significance: Our data unveiled a novel role of miR-27a in EndMT during hypoxia-induced PAH. Thus, targeting of miR-27a-related pathway may be therapeutically harnessed to treat PAH.