Abstract
Hydrogen peroxide (H2O2) or 4-hydroxy-2,3-trans-nonenal (HNE) treatment of rat vascular smooth muscle cells (A7r5) caused induction of aldose reductase mRNA. Induction was dose (10-100 microM H2O2, 1-10 microM HNE) and time dependent, reaching a maximum (three- to fourfold) after 7-12 h. Treatment of cells with actinomycin D confirmed de novo synthesis of aldose reductase mRNA. H2O2-induced expression was prevented by catalase but unaffected by Desferal, indicating that metal catalyzed degradation of peroxide was not involved. Induction of enzymatically active aldose reductase by H2O2 and HNE was confirmed using Western blotting and enzyme assays. Aldose reductase can metabolize several aldehyde compounds including HNE, a major toxic product of lipid peroxidation. Inclusion of Sorbinil, an aldose reductase inhibitor, in toxicity assays resulted in a significant (twofold) enhancement of HNE-mediated killing of A7r5 cells, suggesting a protective role of aldose reductase against HNE-induced cell death. These data indicate that the induction of aldose reductase during oxidative stress might represent an important cellular antioxidant defense mechanism.
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