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MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells.

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posted on 10.06.2016 by Y Zeng, X Zhang, K Kang, J Chen, Z Wu, J Huang, W Lu, Y Chen, J Zhang, Z Wang, Y Zhai, J Qu, R Ramchandran, JU Raj, J Wang, D Gou
There is growing evidence that microRNAs are implicated in pulmonary arterial hypertension (PAH), but underlying mechanisms remain elusive. Here, we identified that miR-223 was significantly downregulated in chronically hypoxic mouse and rat lungs, as well as in pulmonary artery and pulmonary artery smooth muscle cells (PASMC) exposed to hypoxia. Knockdown of miR-223 increased PASMC proliferation. In contrast, miR-223 overexpression abrogated cell proliferation, migration and stress fiber formation. Administering miR-223 agomir in vivo antagonized hypoxia-induced increase in pulmonary artery pressure and distal arteriole muscularization. RhoB, which was increased by hypoxia, was identified as one of the targets of miR-223. Overexpressed miR-223 suppressed RhoB and inhibited the consequent phosphorylation of myosin phosphatase target subunit (MYPT1) and the expression of myosin light chain of myosin II (MLC2), which was identified as another target of miR-223. Furthermore, serum miR-223 levels were decreased in female patients with PAH associated with congenital heart disease. Our study provides the first evidence that miR-223 can regulate PASMC proliferation, migration, and actomyosin reorganization through its novel targets, RhoB and MLC2, resulting in vascular remodeling and the development of PAH. It also highlights miR-223 as a potential circulating biomarker and a small molecule drug for diagnosis and treatment of PAH.

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This study was supported by National Natural Science Foundation of China [81170047, 81370151 and 81570046 to D.G., 81173112, 81470246, 81170052 and 81220108001 to J.W., and 31571199 to K.K.]; National Basic Research Program of China 973 Program [2012CB124701 to D.G.]; Shenzhen Municipal Basic Research Program [JC201006010725A to D.G.]; Interdisciplinary Innovation Team Project of Shenzhen University; Shenzhen Overseas High-Level Talents Innovation Program [YFZZ20111009 to D.G.]; Shenzhen High-tech Development Project [CXZZ20140828163951592 to D.G.]; Shenzhen Municipal Basic Research Program [JCYJ20130329120507746 to K.K.]; and Shenzhen University Foundation [201562 to K.K.]. Funding for open access charge: National Natural Science Foundation of China.

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Publisher Statement

This is a copy of an article published in Scientific Reports © 2016 Nature Publishing Group. © The Authors.

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Nature Publishing Group

Language

en_US

issn

2045-2322

Issue date

28/04/2016

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