Superoxide potently induces ceramide formation in glomerular endothelial cells |
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Authors: | Huwiler A Böddinghaus B Pautz A Dorsch S Franzen R Briner V A Brade V Pfeilschifter J |
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Institution: | Pharmazentrum Frankfurt, Institute of Medical Microbiology, Klinikum der Johann Wolfgang Goethe-Universit?t, Theodor-Stern-Kai 7, Frankfurt am Main, D-60590, Germany. |
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Abstract: | Recent evidence suggests that the sphingolipid-derived second messenger ceramide and oxidative stress are intimately involved in apoptosis induction. Here we report that exposure of microcapillary glomerular endothelial cells to superoxide-generating substances, including hypoxanthine/xanthine oxidase and the redox cyclers DMNQ and menadione results in a dose-dependent and delayed increase in the lipid signaling molecule ceramide. Long-term incubation of endothelial cells for 2-30 h with either DMNQ or hypoxanthine/xanthine oxidase leads to a continuous increase in ceramide levels. In contrast, short-term stimulation for 1 min up to 1 h had no effect on ceramide formation. The DMNQ-induced delayed ceramide formation is dose-dependently inhibited by reduced glutathione, whereas oxidized glutathione was without effect. Furthermore, N-acetylcysteine completely blocks DMNQ-induced ceramide formation. All superoxide-generating substances were found to dose-dependently trigger endothelial cell apoptosis. In addition, glutathione and N-acetylcysteine also prevented superoxide-induced apoptosis and implied that ceramide represents an important mediator of superoxide-triggered cell responses like apoptosis. |
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