STRUCTURAL REQUIREMENTS FOR INHIBITION OF CYTOKINE-INDUCED ENDOTHELIAL ACTIVATION BY UNSATURATED FATTY-ACIDS

Dietary long-chain fatty acids (FA) may influence pathological process es involving endothelial activation, including inflammation and athero sclerosis. We have previously shown that the n-3 FA docosahexaenoate ( DHA) inhibits endothelial activation in the range of nutritionally ach ievable plasma concentrations, The present study assessed structural d eterminants for this effect. Saturated, monounsaturated, and n-6 and n -3 polyunsaturated FA were incubated with cultured endothelial cells f or 24-72 h alone, and then in the presence of interleukin-l, tumor nec rosis factor, or bacterial lipopolysaccharide for an additional 24 h b efore assessing the expression of the vascular cell adhesion molecule- 1 (VCAM-1) or other products of endothelial activation. No FA tested p er se elicited endothelial activation. While saturated FA did not inhi bit cytokine-induced expression of adhesion molecules, a progressively increasing inhibitory activity was observed, for the same chain lengt h, with an increase in double bonds. Comparison of FA with the same le ngth and number of unsaturation and only differing for the double bond position or for the cis/trans configuration indicated no difference i n inhibitory potency, indicating no effect of the double bond position or configuration. As judged by Northern analysis, these latter FA als o inhibited VCAM-1 messenger RNA steady state levels to the same exten t, indicating a pre-translational site of action attributable to the s ingle double bond. Thus the double bond is the minimum necessary and s ufficient requirement for FA inhibition of endothelial activation. The se properties are likely relevant to the anti-atherogenic and anti-inf lammatory properties ascribed to n-3 FA, which are able to accommodate the highest number of double bonds in a fatty acid of given chain len gth.