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.
De Caterina
R
R
CNR Institute of Clinical Physiology, Pisa, Italy. RDeCater@po.ifc.pi.cnr. it
Spiecker
M
M
Solaini
G
G
Basta
G
G
Bosetti
F
F
Libby
P
P
Liao
J
J
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