miRNA-34a promotes proliferation of human pulmonary artery smooth muscle cells by targeting PDGFRA.
OBJECTIVE
Pulmonary arterial hypertension (PAH) is a fast progressing vascular disease characterized by uncontrolled cell proliferation of pulmonary artery smooth muscle cells (PASMCs). Some studies have suggested that PAH and cancers share an apoptosis-resistant state, featuring excessive cell proliferation. The miR-34 family consists of tumour-suppressive miRNAs, and its reduced expression has been reported in numerous cancers; however, its role in hypoxia-induced PAH has not been previously studied.


METHODS
miR-34 family expression was evaluated in a rat model with hypoxia and in cultured hypoxic PASMCs, using real-time quantitative PCR (RT-qPCR). Function of miR-34 family was assessed by transfecting miR-34 mimics and inhibitors. Dual luciferase reporter gene assays, RT-qPCR and Western blotting were performed to validate target genes of miR-34.


RESULTS
Significant down-regulation of miR-34a in hypoxic lung tissue, pulmonary artery and PASMCs was identified and then effects of miR-34a in modulating cell proliferation in human pulmonary artery smooth muscle cells (hPASMCs) was investigated in vitro. Reduction of miR-34a levels in hPASMCs caused increased proliferation and these effects were reversed by overexpression of miR-34a. miR-34a overexpression down-regulated platelet-derived growth factor receptor alpha (PDGFRA) expression, which is a key factor in PAH development. These results suggest that miR-34a is a potential regulator of proliferation in PASMCs, and that it could be used as a novel treatment strategy in PAH.
Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China.|Department of Physiology, College of Basic Medical Sciences, Harbin Medical University-Daqing, Daqing, China.
Peng
P
Wang
Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China.
Jie
J
Xu
Department of Emergency Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, China.
Zhiling
Z
Hou
Department of Pathophysiology, College of Basic Medical Sciences, Jiamusi University, Jiamusi, China.
Fangfang
F
Wang
Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China.
Yingli
Y
Song
Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China.
Jiao
J
Wang
Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China.
Hui
H
Zhu
Department of Physiology, College of Basic Medical Sciences, Harbin Medical University, Harbin, China.
Hongbo
H
Jin
D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D019925:Cyclin A / Q000032:analysis / Q000378:metabolism; D019927:Cyclin E / Q000032:analysis / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics; D011651:Pulmonary Artery / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D019925:Cyclin A; D019927:Cyclin E; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D020796:Receptor, Platelet-Derived Growth Factor alpha