The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC epsilon inhibition.
A high intake of the omega-3 fatty acid docosahexaenoate [docosahexaenoic acid (DHA)] has been associated with systemic antiinflammatory effects and cardiovascular protection. Cyclooxygenase (COX)-2 is responsible for the overproduction of prostaglandins (PG) at inflammatory sites, and its expression is increased in atheroma. We studied the effects of DHA on COX-2 expression and activity in human saphenous vein endothelial cells challenged with proinflammatory stimuli. A>or=24-h exposure to DHA reduced COX-2 expression and activity induced by IL-1, without affecting COX-1 expression. DHA effect depended on the NF-kappaB-binding site in the COX-2 promoter. EMSAs confirmed that DHA attenuated NF-kappaB activation. Because MAPK, PKC, and NAD(P)H oxidase all participate in IL-1-mediated COX-2 expression, we also tested whether these enzymes were involved in DHA effects. Western blots showed that DHA blocked nuclear p65 NF-kappaB subunit translocation by decreasing cytokine-stimulated reactive oxygen species and ERK1/2 activation by effects on both NAD(P)H oxidase and PKCepsilon activities. Finally, to address the question whether DHA itself or DHA-derived products were responsible for these effects, we inhibited the most important enzymes involved in polyunsaturated fatty acid metabolism, showing that 15-lipoxygenase-1 products mediate part of DHA effects. These studies provide a mechanistic basis for antiinflammatory and possibly plaque-stabilizing effects of DHA.
Massaro
Marika
M
Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche, 73100 Lecce, Italy.
Habib
Aida
A
Lubrano
Laura
L
Del Turco
Serena
S
Lazzerini
Guido
G
Bourcier
Todd
T
Weksler
Babette B
BB
De Caterina
Raffaele
R
D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors*
D052246:Cyclooxygenase 2 Inhibitors; D004281:Docosahexaenoic Acids; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D051744:Protein Kinase C-epsilon