LINOLEIC-ACID ACTIVATES NUCLEAR TRANSCRIPTION FACTOR-KAPPA-B (NF-KAPPA-B) AND INDUCES NF-KAPPA-B-DEPENDENT TRANSCRIPTION IN CULTURED ENDOTHELIAL-CELLS

High dietary intakes of unsaturated fats may be atherogenic by disrupt ing normal functions of the vascular endothelium, due in part to the a bility of linoleic acid (18:2n-6) to contribute to an increase in cell ular oxidative stress and related injurious events. Exposing endotheli al cells to 90 mu mol linoleic acid/L for 6 h resulted in a significan t increase in lipid hydroperoxides that coincided with an increase in int acellular calcium concentrations. Treatment with this fatty acid c aused an initial decrease in glutathione concentrations, which was fol lowed by an increase at later time points. Most importantly, a signifi cant activation of the oxidative stress-sensitive nuclear transcriptio n factor-kappa B (NF-kappa B) was achieved after a 6-h exposure to 18. 2n-6, which is the time point at which maximal depletion of cellular g lutathione was observed. The fatty acid-mediated NF-kappa B activation was accompanied by induction of NF-kappa B-dependent transcription, a s measured by chloramphenicol acetyltransferase (CAT) assay of an NF-K B-responsive promoter construct. Pretreatment of endothelial cells wit h vitamin E and N-acetyl cysteine inhibited the fatty acid-induced act ivation of NF-kappa B and formation of lipid hydroperoxides. These dat a suggest that oxidative stress-induced cellular changes are critical early events in fatty acid-mediated endothelial cell dysfunction.