title: Arginase II is a target of miR-17-5p and regulates miR-17-5p expression in human pulmonary artery smooth muscle cells.
abstract: Vascular remodeling and smooth muscle cell proliferation are hallmark pathogenic features of pulmonary artery hypertension. MicroRNAs, endogenously expressed small noncoding RNAs, regulate gene expression at the posttranscriptional level. It has previously been shown that miR-17 overexpression in cultured human pulmonary artery smooth muscle cell (hPASMC) resulted in increased viable cell number. Previously, we have found that arginase II promotes hypoxia-induced proliferation in hPASMC. Therefore, we hypothesized that miR-17 would be upregulated by hypoxia in hPASMC and would result in greater arginase II expression. We found that levels of miR-17-5p and arginase II were significantly greater in cultured hPASMC exposed to 1% O2 for 48 h than in hPASMC exposed to 21% O2 for 48 h. Furthermore, inhibiting miR-17-5p expression decreased hypoxia-induced arginase II protein levels in hPASMC. Conversely, overexpressing miR-17-5p resulted in greater arginase II protein levels. Somewhat surprisingly, arginase II inhibition was associated with lower miR-17-5p expression in both normoxic and hypoxic hPASMC, whereas overexpressing arginase II resulted in greater miR-17-5p expression in hPASMC. These findings suggest that hypoxia-induced arginase II expression is not only regulated by miR-17-5p but also that there is a feedback loop between arginase II and miR-17-5p in hPASMC. We also found that the arginase II-mediated regulation of miR-17-5p was independent of either p53 or c-myc. We also found that l-arginine, the substrate for arginase II, and l-ornithine, the amino acid product of arginase II, were not involved in the regulation of miR-17-5p expression.
authors.affiliation: Pediatric Intensive Care Unit, Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China; and Pulmonary Hypertension Group, Center for Perinatal Research, Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Youpeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chen
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Trent E
authors.initials: TE
authors.lastname: Tipple
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio Leif.Nelin@nationwidechildrens.org.
authors.forename: Leif D
authors.initials: LD
authors.lastname: Nelin
mesh_terms: D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D005246:Feedback; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; C477631:ARG2 protein, human; D001119:Arginase
keywords: hypoxia; pulmonary hypertension; pulmonary vascular remodeling