MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells.
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.
Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong 518060, China.|Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering Shenzhen University, Shenzhen, Guangdong 518060, China.
Yan
Y
Zeng
Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong 518060, China.
Xiaoying
X
Zhang
Department of Physiology, Shenzhen University Health Science Center, Shenzhen, Guangdong 518060, China.
Kang
K
Kang
Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong 518060, China.
Jidong
J
Chen
Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong 518060, China.
Zhiqin
Z
Wu
Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong 518060, China.
Jinyong
J
Huang
Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong 510120, China.
Wenju
W
Lu
Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong 510120, China.
Yuqin
Y
Chen
Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong 510120, China.
Jie
J
Zhang
Department of Cardiovascular Surgery, Shenzhen Sun Yat-Sen Cardiovascular Hospital, Shenzhen, Guangdong 518060, China.
Zhiwei
Z
Wang
Department of Cardiovascular Surgery, Shenzhen Sun Yat-Sen Cardiovascular Hospital, Shenzhen, Guangdong 518060, China.
Yujia
Y
Zhai
Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering Shenzhen University, Shenzhen, Guangdong 518060, China.
Junle
J
Qu
Department of Pediatrics, University of Illinois at Chicago, Chicago, IL 60612, USA.
Ramaswamy
R
Ramchandran
Department of Pediatrics, University of Illinois at Chicago, Chicago, IL 60612, USA.
J Usha
JU
Raj
Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong 510120, China.|Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Jian
J
Wang
Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong 518060, China.
Deming
D
Gou
D000818:Animals; D024722:Cardiac Myosins / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D000860:Hypoxia; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism*; D051381:Rats; D066253:Vascular Remodeling; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
D024722:Cardiac Myosins; D035683:MicroRNAs; D018994:Myosin Light Chains; D020743:rhoB GTP-Binding Protein; C525067:MIR223, human; C107184:myosin light chain 2