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 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.