title: Angiotensin II suppresses growth arrest specific homeobox (Gax) expression via redox-sensitive mitogen-activated protein kinase (MAPK).
abstract: Oxidative stress is known to be involved in growth control of vascular smooth muscle cells (VSMCs). We and others have demonstrated that angiotensin II (Ang II) has an important role in vascular remodeling. Several reports suggested that VSMC growth induced by Ang II was elicited by oxidative stress. Gax, growth arrest-specific homeobox is a homeobox gene expressed in the cardiovascular system. Over expression of Gax is demonstrated to inhibit VSMC growth. We previously reported that Ang II down-regulated Gax expression. To address the regulatory mechanism of Gax, we investigated the significance of oxidative stress in Ang II-induced suppression of Gax expression. We further examined the involvement of mitogen-activated protein kinases (MAPKs), which is crucial for cell growth and has shown to be activated by oxidative stress, on the regulation of Gax expression by Ang II. Ang II markedly augmented intracellular H2O2 production which was decreased by pretreatment with N-acetylcystein (NAC), an anti-oxidant. Ang II and H2O2 decreased Gax expression dose-dependently and these effects were blocked by administration of both NAC and pyrrolidine dithiocarbamate (PDTC), another anti-oxidant. Ang II and H2O2 induced marked activation of extracellular signal-responsive kinase1/2 (ERK1/2), which was blocked by NAC. Ang II and H2O2 also activated p38MAPK, and they were blocked by pre-treatment with NAC. However, the level of activated p38MAPK was quite low in comparison with ERK1/2. Ang II- or H2O2 -induced Gax down-regulation was significantly inhibited by PD98059, an ERK1/2 inhibitor but not SB203580, a p38MAPK inhibitor. The present results demonstrated the significance of regulation of Gax expression by redox-sensitive ERK1/2 activation.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Saito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Jun
authors.initials: J
authors.lastname: Yamashita
authors.forename: Kentaro
authors.initials: K
authors.lastname: Doi
authors.forename: Tae-Hwa
authors.initials: TH
authors.lastname: Chun
authors.forename: Tokuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Mayumi
authors.initials: M
authors.lastname: Inoue
authors.forename: Ken
authors.initials: K
authors.lastname: Masatsugu
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: Naoki
authors.initials: N
authors.lastname: Sawada
authors.forename: Satsuki
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Tojo
authors.forename: Naoko
authors.initials: N
authors.lastname: Tajima
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Hosoya
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C081336:Meox2 protein, rat; D009124:Muscle Proteins; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases