Fatty acid modulation of endothelial activation

Dietary balance of long-chain fatty acids may influence processes involving leukocyte-endothelial interactions, such as atherogenesis and inflammation , that involve increased endothelial expression of leukocyte adhesion molec ules, or endothelial activation. We compared the ability of various saturat ed, monounsaturated, and polyunsaturated fatty acids to modulate endothelia l activation. Consumption of the n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3) reduced endothelial expression of vascular cell adhesion molecule I (VCAM-1), E-selectin, intercellular adhesion molecule 1 (ICAM-1), interle ukin 6 (IL-6), and IL-8 in response to IL-1, IL-4, tumor necrosis factor, o r bacterial endotoxin, with a half-maximal inhibitory concentration (IC50) of 1-25 mu mol, ie, in the range of nutritionally achievable plasma concent rations. The magnitude of this effect paralleled its incorporation into cel lular phospholipids. DHA also reduced the adhesion of human monocytes and m onocytic U937 cells to cytokine-stimulated endothelial cells. These effects were accompanied by a reduction in VCAM-1 messenger RNA, indicating a pret ranslational effect. To assess structural fatty acid determinants of VCAM-1 inhibitory activity, we compared various saturated, monounsaturated, and n -6 and n-3 polyunsaturated fatty acids for their VCAM-1 inhibitory activity . Saturated fatty acids did not inhibit cytokine-induced expression of adhe sion molecules. However, a progressive increase in inhibitory activity was observed with dietary intake of fatty acids with the same chain length but increasing double bonds, ie, from monounsaturated to n-6 and, further, to n -3 fatty acids. Thus, the greater number of double bonds seems critical for the greater activity of n-3 compared with n-6 fatty acids in inhibiting en dothelial activation. These properties are likely to be relevant to the ant iatherogenic and antiinflammatory properties of n-3 fatty acids.