title: Hypoxia-induced glucose-6-phosphate dehydrogenase overexpression and -activation in pulmonary artery smooth muscle cells: implication in pulmonary hypertension.
abstract: Severe pulmonary hypertension is a debilitating disease with an alarmingly low 5-yr life expectancy. Hypoxia, one of the causes of pulmonary hypertension, elicits constriction and remodeling of the pulmonary arteries. We now know that pulmonary arterial remodeling is a consequence of hyperplasia and hypertrophy of pulmonary artery smooth muscle (PASM), endothelial, myofibroblast, and stem cells. However, our knowledge about the mechanisms that cause these cells to proliferate and hypertrophy in response to hypoxic stimuli is still incomplete, and, hence, the treatment for severe pulmonary arterial hypertension is inadequate. Here we demonstrate that the activity and expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, are increased in hypoxic PASM cells and in lungs of chronic hypoxic rats. G6PD overexpression and -activation is stimulated by H2O2. Increased G6PD activity contributes to PASM cell proliferation by increasing Sp1 and hypoxia-inducible factor 1α (HIF-1α), which directs the cells to synthesize less contractile (myocardin and SM22α) and more proliferative (cyclin A and phospho-histone H3) proteins. G6PD inhibition with dehydroepiandrosterone increased myocardin expression in remodeled pulmonary arteries of moderate and severe pulmonary hypertensive rats. These observations suggest that altered glucose metabolism and G6PD overactivation play a key role in switching the PASM cells from the contractile to synthetic phenotype by increasing Sp1 and HIF-1α, which suppresses myocardin, a key cofactor that maintains smooth muscle cell in contractile state, and increasing hypoxia-induced PASM cell growth, and hence contribute to pulmonary arterial remodeling and pathogenesis of pulmonary hypertension.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama;
authors.forename: Sukrutha
authors.initials: S
authors.lastname: Chettimada
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama;
authors.forename: Rakhee
authors.initials: R
authors.lastname: Gupte
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama;
authors.forename: Dhwajbahadur
authors.initials: D
authors.lastname: Rawat
authors.affiliation: Department of Cell Biology and Neurosciences, College of Medicine, University of South Alabama, Mobile, Alabama;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Gebb
authors.affiliation: Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama; Department of Medicine, College of Medicine, University of South Alabama, Mobile, Alabama; and Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama; Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama s_gupte@nymc.edu.
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Gupte
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D049109:Cell Proliferation; D004790:Enzyme Induction; D015870:Gene Expression; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000201:enzymology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D009687:Nuclear Proteins / Q000378:metabolism; D014176:Protein Biosynthesis; D011651:Pulmonary Artery / Q000473:pathology*; D051381:Rats; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D000099251:Myocardin
chemical_list: D018797:Cell Cycle Proteins; D005954:Glucosephosphate Dehydrogenase; D006861:Hydrogen Peroxide; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D000099251:Myocardin; C497444:Hif1a protein, rat
keywords: HIF-1α; KLF; NADPH; SM22α; Sp1; cell cycle; myocardin; reactive oxygen species; redox; smooth muscle phenotype