Jt. Shin et al., ACIDIC FIBROBLAST GROWTH-FACTOR ENHANCES PEROXYNITRITE-INDUCED APOPTOSIS IN PRIMARY MURINE FIBROBLASTS, Archives of biochemistry and biophysics, 335(1), 1996, pp. 32-41
Oxidative stress is considered a major mediator of apoptosis in severa
l cellular systems. Peroxynitrite is a highly toxic oxidant formed by
the reaction of nitric oxide with superoxide. Primary embryonic murine
fibroblasts, exposed to 1 mM peroxynitrite, resulted in delayed cell
death characterized by membrane blebbing, cytoplasmic shrinkage, nucle
ar condensation, and DNA fragmentation that were more characteristic o
f apoptosis than necrosis. In addition, both morphological alterations
and DNA fragmentation were inhibited by the endonuclease inhibitor au
rintricarboxylic acid. Pretreatment of fibroblasts with acidic fibrobl
ast growth factor (FGF-1) markedly enhanced peroxynitrite-induced apop
tosis, an observation restricted to immediate-early transcriptional an
d activated tyrosine phosphorylation processes. FGF-1 pretreatment had
no modulatory effect on cell death elicited by other reactive oxygen
species, suggesting that enhancement of apoptosis involves a unique re
lationship between peroxynitrite and the growth factor, Exposure of ce
lls to peroxynitrite resulted in immediate tyrosine nitration of sever
al polypeptides, including major targets with estimated molecular mass
es of 62, 68, and 77 kDa. Pretreatment with FGF-1 did not alter target
s of peroxynitrite-mediated tyrosine nitration, but rather increased t
he total amount of this amino acid modification, Treatment with other
reactive oxygen species failed to induce tyrosine nitration. Collectiv
ely, these efforts demonstrate that FGF-1 transiently renders primary
fibroblasts more sensitive to peroxynitrite-induced apoptosis, In addi
tion, results presented here predict a pivotal role for FGF-1 and pero
xynitrite-induced cytotoxicity during the resolution of inflammation a
nd repair processes in vivo. (C) 1996 Academic Press, Inc.