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Vol. 58, Issue 1, 152-158, July 2000
Department of Physiology and Pharmacology, College of Veterinary
Medicine, Texas A&M University, College Station, Texas
Repeated cycles of vascular injury by benzo(a)pyrene (BaP)
increase the onset and progression of atherosclerotic lesions in laboratory animals. This atherogenic response is partly mediated by
activation of cis-acting antioxidant/electrophile response elements that enhance c-Ha-ras transcription in
vascular smooth muscle cells (vSMCs). Activation of
antioxidant/electrophile responsive cis-acting elements may depend on
metabolism of BaP by cytochrome P450s to intermediates that induce
oxidative stress and modulate gene expression. To test this hypothesis,
we evaluated mitogen-activated c-Ha-ras expression in
vSMCs treated with BaP or its metabolic intermediates alone, and in
combination with agents that modulate cellular redox status. BaP (0.3 and 3 µM), BaP-3,6-quinone (0.3 µM), or hydrogen peroxide (50 µM)
enhanced serum-activated c-Ha-ras. Ellipticine (0.01 nM), a known inhibitor of cytochrome P450 metabolism and aryl
hydrocarbon receptor (AhR) antagonist, inhibited
c-Ha-ras induction by BaP (3 µM). Serum challenge of
G0 synchronized cultures of vSMCs with
DL-buthionine-(S,R)-sulfoximine
(0.1 mM), a depletor of cellular glutathione, increased
c-Ha-ras mRNA levels during the early phase of the
mitogenic response. Combined
BaP/DL-buthionine-(S,R)-sulfoximine challenge was cytotoxic to the cells and inhibited
c-Ha-ras expression, whereas up-regulation of
antioxidant capacity by N-acetylcysteine (0.5 mM)
precluded BaP-induced ras expression. BaP increased
formation of reactive oxygen species and depleted cellular glutathione, but these changes did not correlate with the kinetics of
c-Ha-ras induction. BaP did not enhance
c-Ha-ras expression in vSMCs from AhR knockout mice,
although aryl hydrocarbon hydroxylase activity was constitutively
expressed in these cells. These results suggest that
c-Ha-ras activation in vSMCs by BaP involves a
redox-sensitive mechanism that is coupled to AhR receptor-dependent functions.
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