Cyclooxygenase-2 inhibition increases lipopolysaccharide-induced atherosclerosis in mice.

AIMS The risk of adverse cardiovascular events in humans is increased with chronic use of cyclooxygenase-2 (COX-2) inhibitors. However, the role of COX-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 pro-inflammatory mediators, such as bacterial lipopolysaccharide (LPS), thereby producing a systemic inflammatory response. The current study examined the role of COX-2 in atherosclerosis induced by LPS derived from the periodontal disease pathogen Porphyromonas gingivalis (P. gingivalis). METHODS AND RESULTS Porphyromonas gingivalis LPS was administered by chronic infusion for 28 days and atherosclerosis development was examined in the aortic root of ApoE (apolipoprotein E)-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. Porphyromonas 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 (messenger ribonucleic acid) and the production of prostaglandin (PG) E(2) (PGE(2)), the latter of which was inhibited by celecoxib. Porphyromonas gingivalis LPS-induced expression of tumour necrosis factor alpha (TNFalpha) was enhanced by inactivation of COX-2 and was attenuated by treatment with PGE(2). CONCLUSION The inhibition of COX-2-derived PGE(2) may enhance P. gingivalis LPS-induced atherosclerosis by increasing macrophage production of TNFalpha.