LINOLEIC-ACID AND TNF-ALPHA CROSS-AMPLIFY OXIDATIVE INJURY AND DYSFUNCTION OF ENDOTHELIAL-CELLS

Factors implicated in the development of atherosclerosis include metab olic alterations of the endothelium induced by certain lipids and infl ammatory cytokines. To study the hypothesis that the combined presence of unsaturated fatty acids and inflammatory cytokines may cross-ampli fy their individual injurious effects cultured endothelial cells were treated with 90 mu M of linoleic acid (18:2 n-6) and/or 20 ng/ml (100 U/ml) of tumor necrosis factor-alpha (TNF) for up to 24 h. Disturbance s in endothelial cell metabolism were determined by measuring cellular oxidative stress, oxidative stress-inducible nuclear factor-kappa B ( NF-kappa B) and NF-kappa B-related transcription: intracellular calciu m levels, and endothelial barrier function reflected by transendotheli al albumin movement. Both 18:2 and TSF increased cellular oxidation, i ntracellular calcium, and endothelial barrier permeability. These chan ges were cross-amplified in cells treated both with 18:2 and TNF, comp ared with 18:2 or TNF alone. In contrast, a combined exposure to 18:2 and TNF did not potentiate effects mediated by 18:2 or TNF alone on NF -kappa B activation or NF-kappa B-related transcription. Pretreatment with 25 mu M vitamin E attenuated 18:2 and/or TNF-mediated endothelial cell dysfunction. These results suggest that certain unsaturated fatt y acids can potentiate TNF-mediated endothelial cell dysfunction and t hat oxidative stress may be partially responsible for these metabolic events. These findings have implications for understanding lipid-media ted inflammatory responses in atherosclerosis.