The inhibition of endothelial activation by unsaturated fatty acids.
Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation and leukocyte-endothelial interactions, such as inflammation and atherosclerosis. We previously showed that the n-3 FA docosahexaenoate (22:6n-3, DHA) inhibits cytokine-stimulated expression of endothelial-leukocyte adhesion molecules and soluble cytokines in the range of nutritionally achievable plasma concentrations. More recently we assessed structural determinants of VCAM-1 inhibition by FA. Cultured endothelial cells were incubated first with various saturated, monounsaturated, n-6 or n-3 polyunsaturated FA alone and then together with interleukin-1 or tumor necrosis factor. Saturated FA did not inhibit cytokine-induced endothelial activation, while a progressive increase in inhibitory activity was observed, for the same chain length, with the increase in double bonds accompanying the transition from monounsaturates to n-6 and, further, to n-3 FA. Comparison of various FA indicated no role of the double-bond position or configuration; the greater number of double bonds could explain the greater inhibitory activity of n-3 vs. n-6 FA. In order to ascertain mechanisms for these effects, we demonstrated inhibition of nuclear factor-kappaB (NF-kappaB) activation by DHA in parallel with a reduction in hydrogen peroxide (a critical mediator of NF-kappaB activation) released by endothelial cells either extracellularly or intracellularly. This suggests that a property related to fatty acid peroxidability (the presence of multiple double bonds) is related to inhibitory properties of hydrogen peroxide release and, consequently, of endothelial activation.
CNR Institute of Clinical Physiology, Pisa, Italy. RDeCater@po.ifc.pi.cnr. it
R
R
De Caterina
M
M
Spiecker
G
G
Solaini
G
G
Basta
F
F
Bosetti
P
P
Libby
J
J
Liao
D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000502:physiology
D016207:Cytokines; D004042:Dietary Fats, Unsaturated; D005231:Fatty Acids, Unsaturated; D019010:Vascular Cell Adhesion Molecule-1