title: MicroRNA-30c contributes to the development of hypoxia pulmonary hypertension by inhibiting platelet-derived growth factor receptor β expression.
abstract: Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs). MicroRNAs have been implicated in the regulation of cell proliferation and might be implicated in the etiology of PAH. Data from in vivo and in vitro cell culture models showed that hypoxia inhibits microRNA-30c (miR-30c) expression in PASMCs. Inhibition of miR-30c by either hypoxia or AMO-30c results in PASMC proliferation (cell viability, 5-bromo-2-deoxyuridine (BrdU) incorporation, proliferating cell nuclear antigen, Ki67, and tubulin polymerization) and the inhibition of apoptosis (cell cycle progression, Cyclin A and Cyclin D, and TUNEL staining). Moreover, down-regulation of miR-30c also results in the phenotype switch from contractile to synthetic PASMC (SM22α and Calponin, osteopontin expression, and wound healing assay). In contrast, these effects were reversed by the application of an miR-30c mimetic under hypoxic conditions. Mechanically, miR-30c inhibited the platelet-derived growth factor receptor β (PDGFRβ) expression by directly binding to the 3' untranslated region of PDGFRβ mRNA (luciferase reporter assays, and PDGFRβ-masking antisense oligodeoxynucleotides). Pharmacological inhibition of PDGFR by AG-1296 displayed similar effects to the miR-30c mimetic. These data suggest that the down-regulation of miR-30c accounts for the up-regulation of PDGFRβ expression, and subsequent activation of PDGF signaling results in the hypoxia-induced PASMC proliferation and phenotype switching. Therefore, increasing miR-30c expression levels could be explored as a potential new therapy for hypoxia-induced PAH.
authors.affiliation: Department of Pharmacology, College of Basic Medicine, Harbin Medical University (Daqing), Daqing 163319, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Pathophysiology, College of Basic Medicine, Harbin Medical University (Daqing), Daqing 163319, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, College of Basic Medicine, Harbin Medical University (Daqing), Daqing 163319, China.
authors.forename: Guixia
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing 163319, China; Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liao
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing 163319, China; Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing 163319, China; Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xing
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing 163319, China; Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, 150081, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, 150081, China.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing 163319, China; Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081, China. Electronic address: dalingz@yahoo.com.
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D034622:RNA Interference; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C556157:MIRN30 microRNA, rat; D035683:MicroRNAs; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Phenotype switch; Platelet-derived growth factor receptor β; Proliferation; Pulmonary arterial hypertension; Pulmonary arterial smooth muscle cells; microRNAs-30c