title: The effects of COX-2 selective and non-selective NSAIDs on the initiation and progression of atherosclerosis in ApoE-/- mice.
abstract: In this study, we investigated the effects of prolonged administration of the selective COX-2 inhibitors celecoxib and rofecoxib and the non-selective NSAID naproxen on the initiation and progression of atherosclerosis. ApoE(-/-) mice, as well as corresponding wild-type mice, were fed either a normal chow or a high fat Western diet with or without addition of the respective drugs over a period of 16 weeks. Thereafter, aortic lesion size, plasma lipid levels, and COX-2 expression in the plaques were determined. The results showed that neither the COX-2 selective inhibitors nor naproxen had a significant impact on the initiation and progression of atherosclerosis in diet-fed ApoE(-/-) mice, although both celecoxib and rofecoxib showed a tendency to reduce plaque size. This slight effect may be due to selective inhibition of COX-2 activity because the COX-2 expression was not altered in the plaque. Plasma lipid levels were also not significantly influenced by these drugs. Interestingly, in ApoE(-/-) mice that have been fed with normal chow, we found an increased incidence of plaque formation after treatment with celecoxib and rofecoxib, indicating that coxibs may promote the initiation of atherosclerosis. This effect was probably masked in diet-fed mice by the more pronounced effects of the high cholesterol diet. In conclusion, the reduction in diet-induced plaque size in animals fed a high fat diet and the promotion of atherosclerosis in mice on a normal diet indicate a dual role of the coxibs. In advanced stages of atherosclerosis, they may exert antithrombotic properties due to their COX-2 inhibiting activity, whereas in very early stages they may favor the initiation of atherogenesis. However, because these results were only observed in ApoE(-/-) and not in wild-type animals, coxibs may increase the risk of thrombosis in patients with a predisposition for thrombotic complications.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Metzner
authors.forename: Laura
authors.initials: L
authors.lastname: Popp
authors.forename: Claudiu
authors.initials: C
authors.lastname: Marian
authors.forename: Ronald
authors.initials: R
authors.lastname: Schmidt
authors.forename: Christine
authors.initials: C
authors.lastname: Manderscheid
authors.forename: Christoph
authors.initials: C
authors.lastname: Renne
authors.forename: Beate
authors.initials: B
authors.lastname: Fisslthaler
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Rudi
authors.initials: R
authors.lastname: Busse
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D018450:Disease Progression; D011464:Epoprostenol / Q000097:blood; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D051379:Mice; D013928:Thromboxane A2 / Q000097:blood
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001057:Apolipoproteins E; D018836:Inflammation Mediators; D008055:Lipids; D013928:Thromboxane A2; D011464:Epoprostenol; D051546:Cyclooxygenase 2