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MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1alpha/Fhl-1 pathway

hxt_hz 添加于 2013-6-11 14:58 | 1194 次阅读 | 0 个评论

作者
Yue J, Guan J, Wang X, Zhang L, Yang Z, Ao Q, Deng Y, Zhu P, Wang G
摘要
Hypoxia-induced pulmonary hypertension (PH), which is characterized by vasoconstriction and subsequent structural remodeling of blood vessels, is an important event in chronic obstructive pulmonary disease patients and in people living at high altitudes. Hypoxia-inducible factor-1alpha (HIF-1alpha) and its regulator four-and-a-half LIM (Lin-11, Isl-1 and Mec-3) domain 1 (Fhl-1) have important roles in hypoxia-induced PH. MicroRNA-206 (miR-206) is critical for myogenesis and related diseases; however, the role of miR-206 in hypoxia-induced PH is unknown. miR-206 expression was evaluated in a hypoxic rat model and in cultured hypoxic pulmonary artery smooth muscle cells (PASMCs) using real-time quantitative PCR (RT-qPCR). HIF-1alpha and Fhl-1 expression were evaluated using RT-qPCR, western blotting, immunohistochemistry and immunofluorescence. The function of miR-206 was assessed by transfecting miR-206 mimics and inhibitors. Dual-luciferase reporter gene assays and western blotting were performed to validate the target genes of miR-206. siRNA targeted against Fhl-1 was used to investigate the effect of Fhl-1 on miR-206. Flow cytometry was used to detect the cell cycle phase distribution in each group of PASMCs. Significant downregulation of miR-206 in hypoxic lung tissue and PASMCs was identified, whereas HIF-1alpha and Fhl-1 were upregulated in these samples. The expression of miR-206 in the serum was different from that in the lung tissue. Transfection of pre-miR miR-206 in hypoxic conditions led to increased expression of HIF-1alpha and Fhl-1 rather than abolishing hypoxia-induced HIF-1alpha and Fhl-1, as was expected, and promoted the entry of cells into the S phase and enhanced PASMC proliferation. Fhl-1-targeted siRNA in PASMC prevented cell proliferation and led to an increased proportion of cells in the G1 phase without altering miR-206 expression. Bioinformatic analysis and dual-luciferase reporter gene assays revealed direct evidence for miR-206 targeting of HIF-1alpha. In conclusion, hypoxia-induced downregulation of miR-206 promotes PH by targeting the HIF-1alpha/Fhl-1 pathway in PASMCs. miR-206 could be a triggering factor of early stage of hypoxia-induced PH.Laboratory Investigation advance online publication, 29 April 2013; doi:10.1038/labinvest.2013.63.
详细资料
- 文献种类:期刊
- 期刊名称: Laboratory Investigation; a Journal of Technical Methods and Pathology
- 期刊缩写: Lab Invest
- 期卷页: 2013年
- 地址: 1] Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People\'s Republic of China [2] Department of Pathology, Hubei Cancer Hospital, Wuhan, Hubei Province, People\'s Republic of China [3] Key Laboratory of Respiratory Disease of Ministry of Health, Hubei, China
- ISBN: 0023-6837
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