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The effects of COX-2 selective and non-selective NSAIDs on the initiation and progression of atherosclerosis in ApoE−/− mice

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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.

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Acknowledgment

The authors would like to thank Prof. T. Deller for the use of the laser microdissection equipment.

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Authors and Affiliations

  1. pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany

    Julia Metzner, Laura Popp, Claudiu Marian, Ronald Schmidt, Christine Manderscheid, Christoph Renne, Gerd Geisslinger & Ellen Niederberger

  2. Institut für Kardiovaskuläre Physiologie/ZAFES, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Beate Fisslthaler, Ingrid Fleming & Rudi Busse

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  1. Julia Metzner
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Correspondence to Ellen Niederberger.

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Metzner, J., Popp, L., Marian, C. et al. The effects of COX-2 selective and non-selective NSAIDs on the initiation and progression of atherosclerosis in ApoE−/− mice. J Mol Med 85, 623–633 (2007). https://doi.org/10.1007/s00109-007-0162-9

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  • DOI: https://doi.org/10.1007/s00109-007-0162-9

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