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

Melina R. Kibbe*, Jianrong Li, Suhua Nie, Byung Min Choi, Imre Kovesdi, Alena Lizonova, Timothy R. Billiar, Edith Tzeng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

The functional role of p53 in 1nitric oxide (NO)-mediated vascular smooth muscle cell (VSMC) apoptosis remains unknown. In this study, VSMC from p53-/- and p53+/+ murine aortas were exposed to exogenous or endogenous sources of NO. Unexpectedly, p53-/- VSMC were much more sensitive to the proapoptotic effects of NO than were p53+/+ VSMC. Furthermore, this paradox appeared to be specific to NO, because other proapoptotic agents did not demonstrate this differential effect on p53-/- cells. NO-induced apoptosis in p53-/- VSMC occurred independently of cGMP generation. However, mitogen-activated protein kinase (MAPK) pathways appeared to play a significant role. Treatment of the p53-/- VSMC with S-nitroso-N-acetylpenicillamine resulted in a marked activation of p38 MAPK and, to a lesser extent, of c-Jun NH2-terminal kinase, mitogen-activated protein kinase kinase (MEK) 1/2, and p42/44 (extracellular signal-regulated kinase, ERK). Furthermore, basal activity of the MEK-p42/44 (ERK) pathway was increased in the p53+/+ VSMC. Inhibition of p38 MAPK with SB-203580 or of MEK1/2 with PD-98059 blocked NO-induced apoptosis. Therefore, p53 may protect VSMC against NO-mediated apoptosis, in part, through differential regulation of MAPK pathways.

Original languageEnglish
Pages (from-to)C625-C634
JournalAmerican Journal of Physiology - Cell Physiology
Volume282
Issue number3 51-3
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • Guanosine 3′,5′-cyclic monophosphate
  • Mitogen-activated protein kinase
  • c-Jun NH-terminal kinase
  • p38
  • p42/44

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