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Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 22, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn286
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Cyclooxygenase-2 Inhibition Increases Lipopolysaccharide-Induced Atherosclerosis in Mice

Jonathan M. Gitlin and Charles D. Loftin*

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536

* Correspondence should be addressed to: Dr. Charles D. Loftin, Department of Pharmaceutical Sciences, University of Kentucky, 725 Rose St., Rm. 414, Lexington, KY 40536-0082, Phone: 859-323-9892, Fax: 859-257-7564, Email: cdloft2{at}email.uky.edu

AIMS: The risk of adverse cardiovascular events in humans is increased with chronic use of cyclooxygenase-2 (COX-2) inhibitors. However, the role of cyclooxygenase-2 in animal models of cardiovascular disease has been controversial. In humans and animal models, cardiovascular disease is increased by bacterial infection of the supporting tissue of the teeth, a condition known as periodontal disease. Periodontal disease may result in chronic exposure to proinflammatory mediators, such as bacterial lipopolysaccharide (LPS), thereby producing a systemic inflammatory response. The current study examined the role of cyclooxygenase-2 in atherosclerosis induced by LPS derived from the periodontal disease pathogen P. gingivalis.

METHODS: P. gingivalis LPS was administered by chronic infusion for 28 days and atherosclerosis development was examined in the aortic root of ApoE-deficient mice. The extent of atherosclerosis was compared between mice receiving control diet or diet containing the COX-2 inhibitor celecoxib. The role of COX-2 in P. gingivalis LPS-induced inflammatory cell activation was examined in peritoneal macrophages.

RESULTS: P. gingivalis LPS infusion significantly increased atherosclerosis development. In mice infused with P. gingivalis LPS, administration of the COX-2 inhibitor celecoxib further increased the extent of atherosclerotic lesion area. In peritoneal macrophages, P. gingivalis LPS increased the expression of COX-2 mRNA and the production of prostaglandin E2 (PGE2), the latter of which was inhibited by celecoxib. P. gingivalis LPS-induced expression of tumor necrosis factor alpha (TNFalpha) was enhanced by inactivation of COX-2 and was attenuated by treatment with PGE2.

CONCLUSION: The inhibition of COX-2-derived PGE2 may enhance P. gingivalis LPS-induced atherosclerosis by increasing macrophage production of TNFalpha.

Time for primary review: 15 Days


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