title: Pulmonary artery smooth muscle hypertrophy: roles of glycogen synthase kinase-3beta and p70 ribosomal S6 kinase.
abstract: Increased medial arterial thickness is a structural change in pulmonary arterial hypertension (PAH). The role of smooth muscle hypertrophy in this process has not been well studied. Bone morphogenetic proteins (BMPs), transforming growth factor (TGF)-beta1, serotonin (or 5-hydroxytryptamine; 5-HT), and endothelin (ET)-1 have been implicated in PAH pathogenesis. We examined the effect of these mediators on human pulmonary artery smooth muscle cell size, contractile protein expression, and contractile function, as well on the roles of glycogen synthase kinase (GSK)-3beta and p70 ribosomal S6 kinase (p70S6K), two proteins involved in translational control, in this process. Unlike epidermal growth factor, BMP-4, TGF-beta1, 5-HT, and ET-1 each increased smooth muscle cell size, contractile protein expression, fractional cell shortening, and GSK-3beta phosphorylation. GSK-3beta inhibition by lithium or SB-216763 increased cell size, protein synthesis, and contractile protein expression. Expression of a non-phosphorylatable GSK-3beta mutant blocked BMP-4-, TGF-beta1-, 5-HT-, and ET-1-induced cell size enlargement, suggesting that GSK-3beta phosphorylation is required and sufficient for cellular hypertrophy. However, BMP-4, TGF-beta1, 5-HT, and ET-1 stimulation was accompanied by an increase in serum response factor transcriptional activation but not eIF2 phosphorylation, suggesting that GSK-3beta-mediated hypertrophy occurs via transcriptional, not translational, control. Finally, BMP-4, TGF-beta1, 5-HT, and ET-1 treatment induced phosphorylation of p70S6K and ribosomal protein S6, and siRNAs against p70S6K and S6 blocked the hypertrophic response. We conclude that mediators implicated in the pathogenesis of PAH induce pulmonary arterial smooth muscle hypertrophy. Identification of the signaling pathways regulating vascular smooth muscle hypertrophy may define new therapeutic targets for PAH.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109-5688, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Deng
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
authors.forename: Jing
authors.initials: J
authors.lastname: Lei
authors.forename: Anuli C
authors.initials: AC
authors.lastname: Anyanwu
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
mesh_terms: D000199:Actins / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology; D019332:Endothelin-1 / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006973:Hypertension / Q000473:pathology; D006984:Hypertrophy / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology*; D012701:Serotonin / Q000502:physiology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: D000199:Actins; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019332:Endothelin-1; D007211:Indoles; D008301:Maleimides; D012333:RNA, Messenger; C417521:SB 216763; D053773:Transforming Growth Factor beta1; D012701:Serotonin; D004815:Epidermal Growth Factor; D011189:Potassium Chloride; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride