Hypoxia inducible factor-1 mediates expression of miR-322: potential role in proliferation and migration of pulmonary arterial smooth muscle cells.
Hypoxia inducible factor-1 mediates expression of miR-322: potential role in proliferation and migration of pulmonary arterial smooth muscle cells.
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缺氧诱导因子-1介导miR-322的表达：在肺动脉平滑肌细胞增殖和迁移中的潜在作用
DOI：
10.1038/srep12098
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发表时间：
2015-07-13
影响因子：
4.6
通讯作者：
Gou D
中科院分区：
文献类型：
--
作者：
Zeng Y;Liu H;Kang K;Wang Z;Hui G;Zhang X;Zhong J;Peng W;Ramchandran R;Raj JU;Gou D
越来越多的证据表明microRNA在细胞缺氧反应和肺动脉高压血管重塑中发挥重要作用，但其确切的分子机制尚未完全阐明。在这项研究中，我们确定了miR-322是慢性缺氧小鼠和大鼠肺中诱导的microRNA之一。缺氧后，原代培养的大鼠肺动脉平滑肌细胞（PASMC）中miR-322表达上调。我们证明了HIF-1α，而不是HIF-2α，在缺氧时转录上调miR-322的表达。此外，miR-322促进HIF-1α在细胞核内的聚集，促进缺氧诱导的细胞增殖和迁移。miR-322直接靶向BMPR 1a和smad 5，提示BMP-Smad信号通路的下调可能介导了低氧诱导的PASMC增殖和迁移。我们的研究表明miR-322参与了PASMCs的缺氧增殖反应，这表明它可能在与肺动脉高压相关的肺血管重塑中发挥作用。
There is growing evidence that microRNAs play important roles in cellular responses to hypoxia and in pulmonary hypertensive vascular remodeling, but the exact molecular mechanisms involved are not fully elucidated. In this study, we identified miR-322 as one of the microRNAs induced in lungs of chronically hypoxic mice and rats. The expression of miR-322 was also upregulated in primary cultured rat pulmonary arterial smooth muscle cells (PASMC) in response to hypoxia. We demonstrated that HIF-1α, but not HIF-2α, transcriptionally upregulates the expression of miR-322 in hypoxia. Furthermore, miR-322 facilitated the accumulation of HIF-1α in the nucleus and promoted hypoxia-induced cell proliferation and migration. Direct targeting BMPR1a and smad5 by miR-322 was demonstrated in PASMCs suggesting that downregulation of BMP-Smad signaling pathway may be mediating the hypoxia-induced PASMC proliferation and migration. Our study implicates miR-322 in the hypoxic proliferative response of PASMCs suggesting that it may be playing a role in pulmonary vascular remodeling associated with pulmonary hypertension.
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