title: Essential role of ATF-1 in induction of NOX1, a catalytic subunit of NADPH oxidase: involvement of mitochondrial respiratory chain.
abstract: NADPH oxidase is the major source of superoxide production in cardiovascular tissues. We and others reported that PG (prostaglandin) F2alpha, PDGF (platelet-derived growth factor) and angiotensin II cause hypertrophy of vascular smooth muscle cells by induction of NOX1 (NADPH oxidase 1), a catalytic subunit of NADPH oxidase. We found DPI (diphenylene iodonium), an inhibitor of flavoproteins, including NADPH oxidase itself, almost completely suppressed induction of NOX1 mRNA by PGF2alpha or PDGF in a rat vascular smooth muscle cell line, A7r5. Exploration into the site of action of DPI using various inhibitors suggested the involvement of mitochondrial oxidative phosphorylation in PGF2alpha- or PDGF-induced increase in NOX1 mRNA. In a luciferase reporter assay, activation of the CRE (cAMP-response element)-dependent gene transcription by PGF2alpha was attenuated by oligomycin, an inhibitor of mitochondrial F(o)F1-ATPase. Oligomycin and other mitochondrial inhibitors also suppressed PGF2alpha-induced phosphorylation of ATF (activating transcription factor)-1, a transcription factor of the CREB (CRE-binding protein)/ATF family. Silencing of the ATF-1 gene by RNA interference significantly reduced the induction of NOX1 by PGF2alpha or PDGF, while overexpression of ATF-1 recovered NOX1 induction suppressed by oligomycin. Taken together, ATF-1 may play a pivotal role in the up-regulation of NOX1 in rat vascular smooth muscle cells.
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Katsuyama
authors.forename: ChunYuan
authors.initials: C
authors.lastname: Fan
authors.forename: Noriaki
authors.initials: N
authors.lastname: Arakawa
authors.forename: Toru
authors.initials: T
authors.lastname: Nishinaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyagishi
authors.forename: Kazunari
authors.initials: K
authors.lastname: Taira
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
mesh_terms: D051697:Activating Transcription Factor 1; D000818:Animals; D020134:Catalytic Domain / Q000502:physiology*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015237:Dinoprost / Q000037:antagonists & inhibitors / Q000502:physiology; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology; D020868:Gene Silencing / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000737:chemistry*; D009840:Oligomycins / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D051697:Activating Transcription Factor 1; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009840:Oligomycins; D009861:Onium Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C007517:diphenyleneiodonium; D015237:Dinoprost; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C000614712:NOX1 protein, rat