Nm. Ananyeva et al., OXIDIZED LDL MEDIATES THE RELEASE OF FIBROBLAST GROWTH-FACTOR-I, Arteriosclerosis, thrombosis, and vascular biology, 17(3), 1997, pp. 445-453
Fibroblast growth factor-1 (FGF-1) and lipoproteins play an important
role in atherogenesis. In the present study, we explored a possible me
chanism by which abnormal lipid metabolism could be linked to the prol
iferative aspects of the disease. We tested oxidized LDL (oxLDL) as a
possible pathophysiological mediator of the release of FGF-1, using FG
F-1-transfected mouse NIH 3T3 cells and FGF-1-transfected rabbit smoot
h muscle cells, and compared it with the release caused by elevated te
mperature. Immunoblot analysis showed that oxLDL induced the release o
f FGF-1 in a concentration-dependent manner from 10 to 100 mu g/mL. Th
e effect correlated with the extent of oxidative modification of LDL a
nd was maximal within 4 hours of exposure of cells to oxLDL. In contra
st to the temperature stress-induced FGF-1 secretion pathway, FGF-1 re
leased in response to oxLDL (1) appeared in the conditioned medium as
a monomer: (2) appeared independently of the presence of either actino
mycin D or cycloheximide, and (3) was neither enhanced nor inhibited b
y brefeldin A. We did not detect cell loss, significant morphological
changes, changes in growth characteristics, or other indications of le
thal toxicity in oxLDL-treated cells. Although the level of lactate de
hydrogenase activity was elevated after oxLDL exposure, the calculatio
ns showed that >90% of the FGF-1 was released by viable cells. We prop
ose that oxLDL-induced FGF-1 release is mediated by sublethal and appa
rently transient changes in cell membrane permeability. In the environ
ment of an atherosclerotic lesion, oxLDL-induced FGF-1 release may be
among the mediators of endothelial and smooth muscle cell proliferatio
n.