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.

Anti-Atherosclerotic Effects of Dihomo-.GAMMA.-Linolenic Acid in ApoE-Deficient Mice

“…However, the non-selective COX inhibitor naproxen (10 mg/kg, twice a day) did not affect the atherosclerotic lesions in apoE-deficient mice fed a high-cholesterol diet. The same finding using the same dose of naproxen has been reported in apoE-deficient mice fed a high-cholesterol diet in a previous paper 34) ; however, naproxen negated the decreases of all mRNA levels of p22 phox , gp91 phox , ICAM-1, and VCAM-1 by DGLA treatment. The anti-atherosclerotic effect of HC-DGLA was inhibited by naproxen in the HC-DGLA naproxen group; however, there was no significant difference between the HC-vehicle group and HC-DGLA naproxen group.…”

“…In fact, COX-2 selective inhibitors reduce atherosclerotic lesions in apoE-deficient mice fed a high-cholesterol diet 34) . In the present study, to confirm the contribution of COX metabolites of DGLA to the anti-atherosclerotic effect, the effect of a COX inhibitor, naproxen, was examined in DGLA-treated apoE-deficient mice on a high-cholesterol diet.…”

Celecoxib Combined with Atorvastatin Prevents Progression of Atherosclerosis

“…These results demonstrate the important role of COX-2 in the early development of atherosclerosis and are consistent with our observations that COX-2 inhibition does not alter advanced atherosclerotic lesions. Other studies have also demonstrated that the COX-2 inhibitors celecoxib and rofecoxib did not alter plaque size and COX-2 protein expression in plaque of apo E-/-mice [10,42]. There are conflicting data on the effect of statins on COX-2 expression.…”

Vascular biology of eicosanoids and atherogenesis

“…Two other reports showed that selective blockade of COX-2 activity does not have an impact on advanced atherosclerotic lesions [59,60]. Finally, Metzer et al reported that both celecoxib and rofecoxib had no significant impact on the initiation and progression of atherosclerosis in female apoE-knockout mice [61]. These variable results may be attributable to differences in the experimental models and/or protocols used by various investigators.…”