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PNAS 103 (41): 15184-15189

Copyright © 2006 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC{varepsilon} inhibition

Marika Massaro*,{dagger}, Aida Habib{dagger},{ddagger}, Laura Lubrano§, Serena Del Turco§, Guido Lazzerini§, Todd Bourcier, Babette B. Weksler||, and Raffaele De Caterina**,{dagger}{dagger}

*Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche, 73100 Lecce, Italy; {ddagger}Departments of Biochemistry and Internal Medicine, American University of Beirut, Beirut, Lebanon; §Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche, 56124 Pisa, Italy; Department of Anesthesia, Brigham and Women's Hospital–Harvard Medical School, Boston, MA 02115; ||Weill Medical College of Cornell University, New York, NY 10021; and **Institute of Cardiology and Center of Excellence on Aging, "Gabriele d'Annunzio" University, 66100 Chieti, Italy

Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and approved July 25, 2006

Received for publication January 13, 2006.

Abstract: 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 ≥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-{kappa}B-binding site in the COX-2 promoter. EMSAs confirmed that DHA attenuated NF-{kappa}B 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-{kappa}B subunit translocation by decreasing cytokine-stimulated reactive oxygen species and ERK1/2 activation by effects on both NAD(P)H oxidase and PKC{varepsilon} 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

Key Words: docosahexaenoic acid • endothelium • inflammation • NF-{kappa}B

{dagger}M.M. and A.H. contributed equally to this work.

Author contributions: B.B.W. and R.D.C. designed research; M.M., A.H., L.L., S.D.T., G.L., and T.B. performed research; M.M., A.H., B.B.W., and R.D.C. analyzed data; and B.B.W. and R.D.C. wrote the paper.

Conflict of interest statement: R.D.C. has received research support and honoraria for lecturing on omega-3 fatty acids in cardiovascular disease through Pharmacia-Pfizer (Milan, Italy), Società Prodotti Antibiotici (SPA; Milan, Italy), Sigma-Tau (Pomezia, Italy), and Pronova (Lysaker, Norway).

{dagger}{dagger}To whom correspondence should be addressed. E-mail: rdecater{at}unich.it

© 2006 by The National Academy of Sciences of the USA

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