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

Yan Zeng, Xiaoying Zhang, Kang Kang, Jidong Chen, Zhiqin Wu, Jinyong Huang, Wenju Lu, Yuqin Chen, Jie Zhang, Zhiwei Wang, Yujia Zhai, Junle Qu, Ramaswamy Ramchandran, J. Usha Raj, Jian Wang, Deming Gou

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number24900
JournalScientific Reports
Volume6
DOIs
StatePublished - Apr 28 2016
Externally publishedYes

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MicroRNAs
Pulmonary Artery
Smooth Muscle Myocytes
Pulmonary Hypertension
Lung
Cell Proliferation
Cell Movement
Myosin-Light-Chain Phosphatase
Myosin Type II
Actomyosin
Stress Fibers
Myosin Light Chains
Arterioles
Heart Diseases
Down-Regulation
Biomarkers
Phosphorylation
Vascular Remodeling
Hypoxia
Pressure

ASJC Scopus subject areas

  • General

Cite this

MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells. / Zeng, Yan; Zhang, Xiaoying; Kang, Kang; Chen, Jidong; Wu, Zhiqin; Huang, Jinyong; Lu, Wenju; Chen, Yuqin; Zhang, Jie; Wang, Zhiwei; Zhai, Yujia; Qu, Junle; Ramchandran, Ramaswamy; Usha Raj, J.; Wang, Jian; Gou, Deming.

In: Scientific Reports, Vol. 6, 24900, 28.04.2016.

Research output: Contribution to journalArticle

Zeng, Y, Zhang, X, Kang, K, Chen, J, Wu, Z, Huang, J, Lu, W, Chen, Y, Zhang, J, Wang, Z, Zhai, Y, Qu, J, Ramchandran, R, Usha Raj, J, Wang, J & Gou, D 2016, 'MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells', Scientific Reports, vol. 6, 24900. https://doi.org/10.1038/srep24900
Zeng, Yan ; Zhang, Xiaoying ; Kang, Kang ; Chen, Jidong ; Wu, Zhiqin ; Huang, Jinyong ; Lu, Wenju ; Chen, Yuqin ; Zhang, Jie ; Wang, Zhiwei ; Zhai, Yujia ; Qu, Junle ; Ramchandran, Ramaswamy ; Usha Raj, J. ; Wang, Jian ; Gou, Deming. / MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells. In: Scientific Reports. 2016 ; Vol. 6.
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abstract = "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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