title: Hypoxia induces arginase II expression and increases viable human pulmonary artery smooth muscle cell numbers via AMPKα1signaling.
abstract: Pulmonary artery smooth muscle cell (PASMC) proliferation is one of the hallmark features of hypoxia-induced pulmonary hypertension. With only supportive treatment options available for this life-threatening disease, treating and preventing the proliferation of PASMCs is a viable therapeutic option. A key promoter of hypoxia-induced increases in the number of viable human PASMCs is arginase II, with attenuation of viable cell numbers following pharmacologic inhibition or siRNA knockdown of the enzyme. Additionally, increased levels of arginase have been demonstrated in the pulmonary vasculature of patients with pulmonary hypertension. The signaling pathways responsible for the hypoxic induction of arginase II in PASMCs, however, remain unknown. Hypoxia is a recognized activator of AMPK, which is known to be expressed in human PASMCs (hPASMCs). Activation of AMPK by hypoxia has been shown to promote cell survival in PASMCs. In addition, pharmacologic agents targeting AMPK have been shown to attenuate chronic hypoxia-induced pulmonary hypertension in animal models. The present studies tested the hypothesis that hypoxia-induced arginase II expression in hPASMCs is mediated through AMPK signaling. We found that pharmacologic inhibitors of AMPK, as well as siRNA knockdown of AMPKα1, prevented hypoxia-induced arginase II. The hypoxia-induced increase in viable hPASMC numbers was also prevented following both pharmacologic inhibition and siRNA knockdown of AMPK. Furthermore, we demonstrate that overexpression of AMPK induced arginase II protein expression and viable cells numbers in hPASMCs.
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; and.
authors.forename: Jianjing
authors.initials: J
authors.lastname: Xue
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; and.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Leif D
authors.initials: LD
authors.lastname: Nelin
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; and bernadette.chen@nationwidechildrens.org.|Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chen
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D001119:Arginase / Q000378:metabolism*; D002452:Cell Count; D002470:Cell Survival; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology*; D011651:Pulmonary Artery / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D034741:RNA, Small Interfering; D000263:Adenylate Kinase; C477631:ARG2 protein, human; D001119:Arginase
keywords: l-arginine; pulmonary hypertension; pulmonary vasculature; vascular remodeling; vascular smooth muscle cells