Background— Atherosclerosis has features of an inflammatory disease. Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor–deficient (LDLR^−/−) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR^−/− mice.

Methods and Results— Treatment of male LDLR^−/− mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in the aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1–mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF_1α. Fetal liver cell transplantation was used to generate LDLR^−/− mice null for expression of the COX-2 gene by macrophages. After 8 weeks on the Western diet, COX-2^−/−→LDLR^−/− mice developed significantly less (33% to 39%) atherosclerosis than control COX-2^+/+→LDLR^−/− mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups.

Conclusions— The present studies provide strong pharmacological and genetic evidence that COX-2 promotes early atherosclerotic lesion formation in LDLR^−/− mice in vivo. These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis. (Circulation. 2002;105:1816-1823.)