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Potentiation of nitric oxide-induced apoptosis in p53-/- vascular smooth muscle cells

Melina R Kibbe1, Jianrong Li, Suhua Nie

  • 1Department of Surgery, University of Pittsburgh, 677 Scaife Hall, Pittsburgh, PA 15261, USA. kibbemr@msx.upmc.edu

American Journal of Physiology. Cell Physiology
|February 8, 2002
PubMed

Insights

The tumor suppressor p53 normally protects vascular smooth muscle cells (VSMC) from nitric oxide (NO)-induced cell death. Loss of p53 increases VSMC sensitivity to NO-induced apoptosis, mediated by mitogen-activated protein kinase (MAPK) pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cardiovascular Research

Background:

  • The role of the p53 tumor suppressor in nitric oxide (NO)-mediated apoptosis of vascular smooth muscle cells (VSMC) is not well understood.
  • Nitric oxide plays a critical role in vascular homeostasis and disease.

Purpose of the Study:

  • To investigate the functional role of p53 in NO-mediated VSMC apoptosis.
  • To elucidate the signaling pathways involved in this process.

Main Methods:

  • Vascular smooth muscle cells (VSMC) were isolated from p53 knockout (p53-/-) and wild-type (p53+/+) murine aortas.
  • Cells were exposed to exogenous or endogenous sources of NO.
  • Mitogen-activated protein kinase (MAPK) activation and apoptosis were assessed.
  • Specific MAPK inhibitors were used to block NO-induced apoptosis.

Main Results:

  • p53-/- VSMC exhibited significantly higher sensitivity to NO-induced apoptosis compared to p53+/+ VSMC.
  • This effect was specific to NO and not observed with other proapoptotic agents.
  • NO-induced apoptosis in p53-/- VSMC occurred independently of cyclic guanosine monophosphate (cGMP) generation.
  • NO treatment markedly activated p38 MAPK, c-Jun NH(2)-terminal kinase, MEK1/2, and ERK pathways in p53-/- VSMC.
  • Basal activity of the MEK-ERK pathway was elevated in p53+/+ VSMC.
  • Inhibition of p38 MAPK or MEK1/2 abolished NO-induced apoptosis.

Conclusions:

  • p53 acts as a protective factor against NO-mediated apoptosis in VSMC.
  • This protection is, in part, achieved through the differential regulation of MAPK signaling pathways.
  • These findings reveal a novel mechanism by which p53 influences vascular cell fate in response to NO.

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