Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Deregulated Balance of Omega-6 and Omega-3 Polyunsaturated Fatty Acids following Infection by the Zoonotic Pathogen Streptococcus suis.
C. Lachance, M. Segura, M. C. Dominguez-Punaro, G. Wojewodka, J. B. De Sanctis, D. Radzioch, and M. Gottschalk (2014)
Infect. Immun. 82, 1778-1785
   Abstract »    Full Text »    PDF »
Oral Administration of Eicosapentaenoic Acid or Docosahexaenoic Acid Modifies Cardiac Function and Ameliorates Congestive Heart Failure in Male Rats.
T. T. Yamanushi, H. Kabuto, E. Hirakawa, N. Janjua, F. Takayama, and M. Mankura (2014)
J. Nutr. 144, 467-474
   Abstract »    Full Text »    PDF »
Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4).
X. Li, Y. Yu, and C. D. Funk (2013)
FASEB J 27, 4987-4997
   Abstract »    Full Text »    PDF »
The Role of Essential Fatty Acids in Human Health.
N. R. Glick and M. H. Fischer (2013)
Journal of Evidence-Based Complementary & Alternative Medicine 18, 268-289
   Abstract »    Full Text »    PDF »
Effects of dietary flaxseed on atherosclerotic plaque regression.
A. A. Francis, J. F. Deniset, J. A. Austria, R. K. LaVallee, G. G. Maddaford, T. E. Hedley, E. Dibrov, and G. N. Pierce (2013)
Am J Physiol Heart Circ Physiol 304, H1743-H1751
   Abstract »    Full Text »    PDF »
Platelet Redox Balance in Diabetic Patients With Hypertension Improved by n-3 Fatty Acids.
D. M. McDonald, F. O'Kane, M. McConville, A. B. Devine, and G. E. McVeigh (2013)
Diabetes Care 36, 998-1005
   Abstract »    Full Text »    PDF »
(n-3) Fatty Acids and Cardiovascular Health: Are Effects of EPA and DHA Shared or Complementary?.
D. Mozaffarian and J. H. Y. Wu (2012)
J. Nutr. 142, 614S-625S
   Abstract »    Full Text »    PDF »
Pivotal Role of Protein Kinase C{delta} in Angiotensin II-Induced Endothelial Cyclooxygenase-2 Expression: A Link to Vascular Inflammation.
S. L. Wong, C. W. Lau, W. T. Wong, A. Xu, C. L. Au, C. F. Ng, S. S. M. Ng, M. Gollasch, X. Yao, and Y. Huang (2011)
Arterioscler Thromb Vasc Biol 31, 1169-1176
   Abstract »    Full Text »    PDF »
Docosahexaenoic Acid Improves the Nitroso-Redox Balance and Reduces VEGF-Mediated Angiogenic Signaling in Microvascular Endothelial Cells.
N. Matesanz, G. Park, H. McAllister, W. Leahey, A. Devine, G. E. McVeigh, T. A. Gardiner, and D. M. McDonald (2010)
Invest. Ophthalmol. Vis. Sci. 51, 6815-6825
   Abstract »    Full Text »    PDF »
Novel Lipid Mediators Promote Resolution of Acute Inflammation: Impact of Aspirin and Statins.
M. Spite and C. N. Serhan (2010)
Circ. Res. 107, 1170-1184
   Abstract »    Full Text »    PDF »
Blood Eicosapentaenoic and Docosahexaenoic Acids Predict All-Cause Mortality in Patients With Stable Coronary Heart Disease: The Heart and Soul Study.
J. V. Pottala, S. Garg, B. E. Cohen, M. A. Whooley, and W. S. Harris (2010)
Circ Cardiovasc Qual Outcomes 3, 406-412
   Abstract »    Full Text »    PDF »
PPAR{gamma} agonists inhibit angiogenesis by suppressing PKC{alpha}- and CREB-mediated COX-2 expression in the human endothelium.
E. Scoditti, M. Massaro, M. A. Carluccio, A. Distante, C. Storelli, and R. De Caterina (2010)
Cardiovasc Res 86, 302-310
   Abstract »    Full Text »    PDF »
Statins inhibit cyclooxygenase-2 and matrix metalloproteinase-9 in human endothelial cells: anti-angiogenic actions possibly contributing to plaque stability.
M. Massaro, A. Zampolli, E. Scoditti, M. A. Carluccio, C. Storelli, A. Distante, and R. De Caterina (2010)
Cardiovasc Res 86, 311-320
   Abstract »    Full Text »    PDF »
Adiponectin Promotes Revascularization of Ischemic Muscle through a Cyclooxygenase 2-Dependent Mechanism.
K. Ohashi, N. Ouchi, K. Sato, A. Higuchi, T.-o Ishikawa, H. R. Herschman, S. Kihara, and K. Walsh (2009)
Mol. Cell. Biol. 29, 3487-3499
   Abstract »    Full Text »    PDF »
Eicosapentaenoic Acid Improves Imbalance between Vasodilator and Vasoconstrictor Actions of Endothelium-Derived Factors in Mesenteric Arteries from Rats at Chronic Stage of Type 2 Diabetes.
T. Matsumoto, N. Nakayama, K. Ishida, T. Kobayashi, and K. Kamata (2009)
J. Pharmacol. Exp. Ther. 329, 324-334
   Abstract »    Full Text »    PDF »
Dietary Omega-3 Fatty Acids, Cyclooxygenase-2 Genetic Variation, and Aggressive Prostate Cancer Risk.
V. Fradet, I. Cheng, G. Casey, and J. S. Witte (2009)
Clin. Cancer Res. 15, 2559-2566
   Abstract »    Full Text »    PDF »
Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation.
L. Wang, R. Gill, T. L. Pedersen, L. J. Higgins, J. W. Newman, and J. C. Rutledge (2009)
J. Lipid Res. 50, 204-213
   Abstract »    Full Text »    PDF »
Evaluation of lipid profiles and the use of omega-3 essential Fatty Acid in professional football players..
A. Yates, J. Norwig, J. C. Maroon, J. Bost, J. P. Bradley, M. Duca, D. A. Wecht, R. Grove, A. Iso, I. Cobb, et al. (2009)
Sports Health: A Multidisciplinary Approach 1, 21-30
   Abstract »    Full Text »    PDF »
Electrophilic Cyclopentenone Neuroprostanes Are Anti-inflammatory Mediators Formed from the Peroxidation of the {omega}-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid.
E. S. Musiek, J. D. Brooks, M. Joo, E. Brunoldi, A. Porta, G. Zanoni, G. Vidari, T. S. Blackwell, T. J. Montine, G. L. Milne, et al. (2008)
J. Biol. Chem. 283, 19927-19935
   Abstract »    Full Text »    PDF »
15-Lipoxygenase-1 transcriptional silencing by DNA methyltransferase-1 independently of DNA methylation.
X. Zuo, L. Shen, J.-P. Issa, O. Moy, J. S. Morris, S. M. Lippman, and I. Shureiqi (2008)
FASEB J 22, 1981-1992
   Abstract »    Full Text »    PDF »
Signaling pathways modulated by fish oil in salt-sensitive hypertension.
M. M. Diaz Encarnacion, G. M. Warner, C. E. Gray, J. Cheng, H. K. H. Keryakos, K. A. Nath, and J. P. Grande (2008)
Am J Physiol Renal Physiol 294, F1323-F1335
   Abstract »    Full Text »    PDF »
Cholesterol Sensitivity of Endogenous and Myristoylated Akt.
R. M. Adam, N. K. Mukhopadhyay, J. Kim, D. Di Vizio, B. Cinar, K. Boucher, K. R. Solomon, and M. R. Freeman (2007)
Cancer Res. 67, 6238-6246
   Abstract »    Full Text »    PDF »
n-3 Fatty Acids in the Treatment of Diabetic Patients: Biological rationale and clinical data.
R. De Caterina, R. Madonna, A. Bertolotto, and E. B. Schmidt (2007)
Diabetes Care 30, 1012-1026
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882