The inhibition of endothelial activation by unsaturated fatty acids

Dietary long-chain fatty acids (FA) may influence pathological processes in volving endothelial activation and leukocyte-endothelial interactions, such as inflammation and atherosclerosis. We previously showed that the n-3 FA docosa-hexaenoate (22:6n-3, DHA) inhibits cytokine-stimulated expression of endothelial-leukocyte adhesion molecules and soluble cytokines in the rang e of nutritionally achievable plasma concentrations. More recently we asses sed structural determinants of VCAM-1 inhibition by FA. Cultured endothelia l cells were incubated first with various saturated, monounsaturated, n-6 o r n-3 polyunsaturated FA alone and then together with interleukin-1 or tumo r necrosis factor. Saturated FA did not inhibit cytokine-induced endothelia l activation, while a progressive increase in inhibitory activity was obser ved, for the same chain length, with the increase in double bonds accompany ing the transition from monounsaturates to n-6 and, further, to n-3 FA. Com parison of various FA indicated no role of the double-bond position or conf iguration; the greater number of double bonds could explain the greater inh ibitory activity of n-3 vs. n-6 FA. In order to ascertain mechanisms for th ese effects, we demonstrated inhibition of nuclear factor-kappa B (NF-kappa B) activation by DHA in parallel with a reduction in hydrogen peroxide (a critical mediator of NF-kappa B activation) released by endothelial cells e ither extracellularly or intracellularly. This suggests that a property rel ated to fatty acid peroxidability (the presence of multiple double bonds) i s related to inhibitory properties of hydrogen peroxide release and, conseq uently, of endothelial activation.