Structural requirements for inhibition of cytokine-induced endothelial activation by unsaturated fatty acids

Raffaele De Caterina,Walter Bernini,Maria Annunziata Carluccio,James K Liao,Peter Libby

doi:10.1016/s0022-2275(20)33875-x

Abstract

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation, including inflammation and atherosclerosis. We have previously shown that the n-3 FA docosahexaenoate (DHA) inhibits endothelial activation in the range of nutritionally achievable plasma concentrations. The present study assessed structural determinants for this effect. Saturated, monounsaturated, and n-6 and n-3 polyunsaturated FA were incubated with cultured endothelial cells for 24-72 h alone, and then in the presence of interleukin-1, tumor necrosis factor, or bacterial lipopolysaccharide for an additional 24 h before assessing the expression of the vascular cell adhesion molecule-1 (VCAM-1) or other products of endothelial activation. No FA tested per se elicited endothelial activation. While saturated FA did not inhibit cytokine-induced expression of adhesion molecules, a progressively increasing inhibitory activity was observed, for the same chain length, with an increase in double bonds. Comparison of FA with the same length and number of unsaturation and only differing for the double bond position or for the cis/trans configuration indicated no difference in inhibitory potency, indicating no effect of the double bond position or configuration. As judged by Northern analysis, these latter FA also inhibited VCAM-1 messenger RNA steady state levels to the same extent, indicating a pre-translational site of action attributable to the single double bond. Thus the double bond is the minimum necessary and sufficient requirement for FA inhibition of endothelial activation. These properties are likely relevant to the anti-atherogenic and anti-inflammatory properties ascribed to n-3 FA, which are able to accommodate the highest number of double bonds in a fatty acid of given chain length.

Highlights

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation, including inflammation and atherosclerosis
We recently reported one mechanism by which changes in lipid membrane composition by enrichment of n–3 FA may influence atherogenesis and inflammation
We found that DHA reduces by more than 50% the endothelial responses to certain cytokines or LPS, including expression of adhesion molecules as varied as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, intercellular adhesion molecule-1 (ICAM-1), and soluble mediators of inflammation elicited after endothelial activation, such as IL-6 and IL-8 [13, 14]

Summary

Introduction

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation, including inflammation and atherosclerosis. Examples include the reduction of hepatic synthesis of very low density lipoproteins [10], and the reduction of interleukin-1, tumor necrosis factor [11] and platelet-derived growth factor B-chain expression [12] in endotoxin-activated macrophages by n–3 FA In keeping with these observations, we have shown that nutritionally relevant concentrations of n–3 FA (low micromolar) modulate cytokine-induced expression of endothelial leukocyte adhesion molecules and soluble pro-inflammatory proteins [13, 14]. This effect involves a prostaglandin-independent modulation of steady-state messenger RNA (mRNA) for adhesion molecules and reduced white blood cell adhesion to cytokine-activated endothelium [13, 14].

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