miR-29a-3p Attenuates Hypoxic Pulmonary Hypertension by Inhibiting Pulmonary Adventitial Fibroblast Activation
miR-29a-3p Attenuates Hypoxic Pulmonary Hypertension by Inhibiting Pulmonary Adventitial Fibroblast Activation
复制标题
miR-29a-3p通过抑制肺外膜成纤维细胞活化减轻缺氧性肺动脉高压
DOI：
10.1161/hypertensionaha.114.04600
复制
发表时间：
2015-02-01
期刊：
影响因子：
8.3
通讯作者：
Li, Zhi-Chao
中科院分区：
文献类型：
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作者：
Luo, Ying;Dong, Hai-Ying;Li, Zhi-Chao
缺氧肺动脉高压患者肺血管重构过程中，肺内膜成纤维细胞的活化起关键作用。先前的研究表明，mirna参与了成纤维细胞活化的调控。本研究探讨了miR-29在肺内膜成纤维细胞活化中的作用以及在低氧性肺动脉高压中的治疗潜力。我们发现缺氧诱导的肺外膜成纤维细胞活化伴随着miR-29a-3p表达的急剧下降。缺氧诱导因子1 &agr的表达下调或Smad3可逆转缺氧诱导的培养肺外成纤维细胞中miR-29-3p的降低。在体外，miR-29a-3p模拟物抑制缺氧诱导的肺外成纤维细胞的增殖、迁移和分泌，抑制缺氧诱导的&agr的表达；-肺上皮成纤维细胞中的平滑肌肌动蛋白和细胞外基质胶原；然而，miR-29a-3p抑制剂模拟缺氧对肺内膜成纤维细胞活化的影响。进一步研究发现，预防或治疗性给予miR-29a-3p可显著降低低氧肺动脉高压大鼠肺动脉压和右心室肥厚指数，改善肺血管重构。这些研究结果表明，miR-29a-3p在缺氧条件下调节肺内膜成纤维细胞的活化和表型，在缺氧肺动脉高压中具有预防和治疗潜力。
Activation of pulmonary adventitial fibroblasts plays a key role in the pulmonary vascular remodeling in hypoxic pulmonary hypertension. Previous studies showed that miRNAs participated in the regulation of fibroblast activation. This study explored the role of miR-29 in the activation of pulmonary adventitial fibroblasts and the therapeutic potential in hypoxic pulmonary hypertension. We found that hypoxia-induced pulmonary adventitial fibroblasts activation was accompanied with a drastic decrease of miR-29a-3p expression. Knockdown of hypoxia-inducible factor-1 &agr; or Smad3 reversed the hypoxia-induced decrease of miR-29-3p in cultured pulmonary adventitial fibroblasts. In vitro, miR-29a-3p mimic inhibited the hypoxia-induced proliferation, migration, and secretion of pulmonary adventitial fibroblasts, suppressed the hypoxia-induced expression of &agr;-smooth muscle actin and extracellular matrix collagen in pulmonary adventitial fibroblasts; however, miR-29a-3p inhibitor mimicked the effect of hypoxia on the activation of pulmonary adventitial fibroblasts. Further studies revealed that preventative or therapeutic administration of miR-29a-3p significantly decreased pulmonary artery pressure and right ventricle hypertrophy index and ameliorated pulmonary vascular remodeling in hypoxic pulmonary hypertension rats. These findings suggest that miR-29a-3p regulates the activation and phenotype of pulmonary adventitial fibroblasts in hypoxia and has preventative and therapeutic potential in hypoxic pulmonary hypertension.