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Am J Physiol Cell Physiol 282: C625-C634, 2002. First published October 3, 2001; doi:10.1152/ajpcell.00119.2001
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Vol. 282, Issue 3, C625-C634, March 2002

Potentiation of nitric oxide-induced apoptosis in p53minus /minus vascular smooth muscle cells

Melina R Kibbe1, Jianrong Li1, Suhua Nie1, Byung Min Choi1, Imre Kovesdi2, Alena Lizonova2, Timothy R Billiar1, and Edith Tzeng1

1 Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and 2 GenVec Inc., Gaithersburg, Maryland 20878

The functional role of p53 in nitric 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.

mitogen-activated protein kinase; guanosine 3',5'-cyclic monophosphate, p38; c-Jun NH2-terminal kinase; p42/44


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