Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice

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 fur 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in file 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(1alpha). Fetal liver cell transplantation was used to generate LDLR-/- mice null for expression of the COX-2 gene by macropliages. After 8 weeks on the Western diet, COX-2(-/-)-->LDLR-/- mice developed significantly less (33% to 3917c) 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 earl), atherosclerotic lesion formation in LDLR-/- mice in vivo. These results support the potential of anti-inflamminatory approaches to the prevention of atherosclerosis.