This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rott, D. Articles by Epstein, S. E. Search for Related Content PubMed PubMed Citation Articles by Rott, D. Articles by Epstein, S. E.

BASIC SCIENCE

Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice

^* Cardiovascular Research Institute, Medstar Research Institute, Washington Hospital Center, Washington, DC, USA

Manuscript received July 3, 2002; revised manuscript received January 8, 2003, accepted January 16, 2003.

^* Reprint requests and correspondence: Dr. Stephen E. Epstein, Cardiovascular Research Institute, Washington Hospital Center, 110 Irving Street NW, Suite 4B-1, Washington, DC 20010, USA.
stephen.epstein{at}medstar.net

OBJECTIVES: We examined whether selective cyclooxygenase-2 (COX-2) inhibition in apolipoprotein-E (apoE) deficient mice reduces cytomegalovirus (CMV) replication, and determined whether COX-2 anti-inflammatory activity leads to decreased atherosclerosis.

BACKGROUND: Evidence suggests that CMV infection contributes to atherosclerosis and that this occurs in part through inflammatory mechanisms. Cyclooxygenase-2 inhibitors are potent anti-inflammatory agents. They also inhibit CMV replication in vitro.

METHODS: The apoE deficient mice were either treated or not treated with a selective COX-2 inhibitor, and either infected or not infected with CMV. Viral deoxyribonucleic acid load in salivary glands was determined by quantitative polymerase chain reaction. Atherosclerotic lesion analysis was performed by standard methods.

RESULTS: In vivo COX-2 inhibition, unexpectedly increased viral load: in the CMV-infected animals viral load was 2.58 ± 1.0 in the nontreated group, 4.74 ± 1.38 in the group treated with 12 mg/kg/day MF-tricyclic, and 6.51 ± 1.64 in the group treated with 24 mg/kg/day MF-tricyclic (p trend = 0.050). This increased viral load was paralleled by increased anti-CMV antibody titers. Most surprisingly, COX-2 inhibition significantly increased early atherosclerotic lesion area, independent of viral infection.

CONCLUSIONS: Our study demonstrates that selective inhibition of COX-2 in vivo increases viral load. The finding that inhibition of COX-2 increases atherosclerosis development in apoE deficient mice suggests, unexpectedly, that this enzyme exerts antiatherosclerosis activity, at least in this model.

Abbreviations and Acronyms   apoE   apolipoprotein-E   CMV   cytomegalovirus   COX   cyclooxygenase   DNA   deoxyribonucleic acid   IFN   interferon-gamma   IgG   immunoglobulin-G   IL   interleukin   NFB   nuclear factor kappa-B   PCR   polymerase chain reaction   PG   prostaglandin   ROS   reactive oxygen species   SMCs   smooth muscle cells   TNF   tumor necrosis factor-alpha

This article has been cited by other articles:

				J. M. Gitlin and C. D. Loftin Cyclooxygenase-2 inhibition increases lipopolysaccharide-induced atherosclerosis in mice Cardiovasc Res, February 1, 2009; 81(2): 400 - 407. [Abstract] [Full Text] [PDF]

				E. M. Antman, J. S. Bennett, A. Daugherty, C. Furberg, H. Roberts, and K. A. Taubert Use of Nonsteroidal Antiinflammatory Drugs: An Update for Clinicians: A Scientific Statement From the American Heart Association Circulation, March 27, 2007; 115(12): 1634 - 1642. [Full Text] [PDF]

				S Moncada Adventures in vascular biology: a tale of two mediators Phil Trans R Soc B, May 29, 2006; 361(1469): 735 - 759. [Abstract] [Full Text] [PDF]

				V. L. King, D. B. Trivedi, J. M. Gitlin, and C. D. Loftin Selective Cyclooxygenase-2 Inhibition With Celecoxib Decreases Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1137 - 1143. [Abstract] [Full Text] [PDF]

				E. M. Antman, D. DeMets, and J. Loscalzo Cyclooxygenase Inhibition and Cardiovascular Risk Circulation, August 2, 2005; 112(5): 759 - 770. [Full Text] [PDF]

				J. S. Bennett, A. Daugherty, D. Herrington, P. Greenland, H. Roberts, and K. A. Taubert The Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): A Science Advisory From the American Heart Association Circulation, April 5, 2005; 111(13): 1713 - 1716. [Full Text] [PDF]

				K. M. Egan, M. Wang, M. B. Lucitt, A. M. Zukas, E. Pure, J. A. Lawson, and G. A. FitzGerald Cyclooxygenases, Thromboxane, and Atherosclerosis: Plaque Destabilization by Cyclooxygenase-2 Inhibition Combined With Thromboxane Receptor Antagonism Circulation, January 25, 2005; 111(3): 334 - 342. [Abstract] [Full Text] [PDF]

				K. S. Michelsen, M. H. Wong, P. K. Shah, W. Zhang, J. Yano, T. M. Doherty, S. Akira, T. B. Rajavashisth, and M. Arditi Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E PNAS, July 20, 2004; 101(29): 10679 - 10684. [Abstract] [Full Text] [PDF]

				K. S. Meir and E. Leitersdorf Atherosclerosis in the Apolipoprotein E-Deficient Mouse: A Decade of Progress Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1006 - 1014. [Abstract] [Full Text] [PDF]

				F. Cipollone, B. Rocca, and C. Patrono Cyclooxygenase-2 Expression and Inhibition in Atherothrombosis Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 246 - 255. [Abstract] [Full Text]

				O. A. Belton, A. Duffy, S. Toomey, and D. J. Fitzgerald Cyclooxygenase Isoforms and Platelet Vessel Wall Interactions in the Apolipoprotein E Knockout Mouse Model of Atherosclerosis Circulation, December 16, 2003; 108(24): 3017 - 3023. [Abstract] [Full Text] [PDF]

				S. Verma and P. E. Szmitko Coxibs and the endothelium J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1754 - 1756. [Full Text] [PDF]