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

Takatoshi Saito1, Hiroshi Itoh, Jun Yamashita

  • 1Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.

Regulatory Peptides
|February 1, 2005
PubMed

Insights

Angiotensin II (Ang II) down-regulates Gax expression in vascular smooth muscle cells (VSMCs) via oxidative stress and extracellular signal-responsive kinase 1/2 (ERK1/2) activation. Antioxidants and ERK1/2 inhibitors block this effect, highlighting redox-sensitive pathways in VSMC growth control.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Molecular Medicine

Background:

  • Oxidative stress influences vascular smooth muscle cell (VSMC) growth.
  • Angiotensin II (Ang II) plays a key role in vascular remodeling, with its VSMC growth effects potentially mediated by oxidative stress.
  • Gax, a homeobox gene in the cardiovascular system, inhibits VSMC growth, and its expression is downregulated by Ang II.

Purpose of the Study:

  • To investigate the role of oxidative stress in Ang II-induced suppression of Gax expression.
  • To examine the involvement of mitogen-activated protein kinases (MAPKs) in the regulation of Gax expression by Ang II.

Main Methods:

  • Assessed intracellular hydrogen peroxide (H2O2) production in response to Ang II.
  • Investigated the effects of antioxidants (N-acetylcystein, pyrrolidine dithiocarbamate) on Ang II- and H2O2-induced Gax expression changes.
  • Analyzed the activation of extracellular signal-responsive kinase 1/2 (ERK1/2) and p38MAPK using Western blotting.
  • Utilized specific inhibitors (PD98059 for ERK1/2, SB203580 for p38MAPK) to determine pathway involvement.

Main Results:

  • Ang II significantly increased intracellular H2O2 production, an effect attenuated by N-acetylcystein (NAC).
  • Both Ang II and H2O2 dose-dependently decreased Gax expression, with effects blocked by NAC and pyrrolidine dithiocarbamate (PDTC).
  • Ang II and H2O2 activated ERK1/2 and p38MAPK; activation was blocked by NAC. ERK1/2 activation was more pronounced than p38MAPK.
  • Inhibition of ERK1/2 (but not p38MAPK) significantly blocked Ang II- or H2O2-induced Gax downregulation.

Conclusions:

  • Oxidative stress is a critical mediator of Ang II-induced Gax suppression in VSMCs.
  • Redox-sensitive activation of ERK1/2 plays a significant role in regulating Gax expression by Ang II.
  • These findings elucidate a novel mechanism linking oxidative stress, MAPKs, and Gax in vascular cell growth regulation.

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