title: Resveratrol prevents hypoxia-induced arginase II expression and proliferation of human pulmonary artery smooth muscle cells via Akt-dependent signaling.
abstract: Pulmonary artery smooth muscle cell (PASMC) proliferation plays a fundamental role in the vascular remodeling seen in pulmonary hypertensive diseases associated with hypoxia. Arginase II, an enzyme regulating the first step in polyamine and proline synthesis, has been shown to play a critical role in hypoxia-induced proliferation of human PASMC (hPASMC). In addition, there is evidence that patients with pulmonary hypertension have elevated levels of arginase in the vascular wall. Resveratrol, a natural polyphenol found in red wine and grape skins, has diverse biochemical and physiological actions including antiproliferative properties. Furthermore, resveratrol has been shown to attenuate right ventricular and pulmonary artery remodeling, both pathological components of pulmonary hypertension. The present studies tested the hypothesis that resveratrol would prevent hypoxia-induced pulmonary artery smooth muscle cell proliferation by inhibiting hypoxia-induced arginase II expression. Our data indicate that hypoxia-induced hPASMC proliferation is abrogated following treatment with resveratrol. In addition, the hypoxic induction of arginase II was directly attenuated by resveratrol treatment. Furthermore, we found that the inhibitory effect of resveratrol on arginase II in hPASMC was mediated through the PI3K-Akt signaling pathway. Supporting these in vitro findings, resveratrol normalized right ventricular hypertrophy in an in vivo neonatal rat model of chronic hypoxia-induced pulmonary hypertension. These novel data support the notion that resveratrol may be a potential therapeutic agent in pulmonary hypertension by preventing PASMC arginase II induction and proliferation.
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University, Columbus, Ohio bernadette.chen@nationwidechildrens.org.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chen
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Jianjing
authors.initials: J
authors.lastname: Xue
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Meng
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; and.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Slutzky
authors.affiliation: Pulmonary Hypertension Group, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Calvert
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; and Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Louis G
authors.initials: LG
authors.lastname: Chicoine
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000209:etiology; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D013267:Stilbenes; D051057:Proto-Oncogene Proteins c-akt; C113162:Arg2 protein, rat; D001119:Arginase; D000077185:Resveratrol
keywords: phosphatidylinositol 3-kinase; pulmonary hypertension; pulmonary vasculature; stilbene; vascular smooth muscle cells