Angiotensin II suppresses growth arrest specific homeobox (Gax) expression via redox-sensitive mitogen-activated protein kinase (MAPK)

Takatoshi Saito, Hiroshi Itoh, Jun Yamashita, Kentaro Doi, Tae Hwa Chun, Tokuji Tanaka, Mayumi Inoue, Ken Masatsugu, Yasutomo Fukunaga, Naoki Sawada, Satsuki Sakaguchi, Hiroshi Arai, Katsuyoshi Tojo, Naoko Tajima, Tatsuo Hosoya, Kazuwa Nakao

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


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 H 2O2 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 H2O 2 induced marked activation of extracellular signal-responsive kinase1/2 (ERK1/2), which was blocked by NAC. Ang II and H2O 2 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.

Original languageEnglish
Pages (from-to)159-167
Number of pages9
JournalRegulatory Peptides
Issue number1-3
Publication statusPublished - 2005 Apr 15
Externally publishedYes


  • Angiotensin II
  • Gax
  • Mitogen-activated protein kinase
  • Oxidative stress
  • Vascular smooth muscle cell

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Clinical Biochemistry
  • Cellular and Molecular Neuroscience


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