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.)

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We have previously reported that the introduction of macrophage apoE into mice lacking both apoE and the LDL receptor (apoE ؊ / ؊ /LDLR ؊ / ؊ ) through bone marrow transplantation (apoE ؉ / ؉ /LDLR ؊ / ؊ → apoE ؊ / ؊ /LDLR ؊ / ؊ ) produces progressive accumulation of apoE in plasma without affecting lipid levels. This model provides a tool to study the effects of physiologically regulated amounts of macrophage apoE on atherogenesis in hyperlipidemic animals. Ten-week-old male apoE ؊ / ؊ /LDLR ؊ / ؊ mice were transplanted with either apoE ؉ / ؉ /LDLR ؊ / ؊ (n ‫؍‬ 11) or apoE ؊ / ؊ / LDLR ؊ / ؊ (n ‫؍‬ 14) marrow. Although there were no differences between the two groups in lipid levels at baseline or at 5 and 9 weeks after transplantation, apoE levels in the apoE ؉ / ؉ LDLR ؊ / ؊ → apoE ؊ / ؊ /LDLR ؊ / ؊ mice increased to 4 times the apoE levels of normal mice. This resulted in a 60% decrease in aortic atherosclerosis in the apoE Although apolipoprotein E (apoE) of macrophage origin is fully functional in its ability to induce the clearance of plasma lipoproteins, substantial evidence supports the concept of a direct anti-atherogenic effect of apoE in the arterial wall. Strong support of a direct effect of apoE in the artery wall comes from bone marrow transplantation studies (1, 2). We have reported that the lack of macrophage apoE in C57BL/6 mice increases the size of diet-induced arterial lesions by 10-fold in the absence of differences in plasma lipoprotein levels (3). We have also shown that apoE Ϫ / Ϫ macrophages increase lesion size in apoA-I deficient and apoA-I over-expressing mice (4). In addition, using a retroviral transduction system, we have shown that low level expression of apoE from macrophages has a strong anti-atherogenic effect during foam cell lesion formation, but this effect was lost when the plaques grew larger and more complex, an indication that the protective capacity of apoE is eventually overwhelmed by the severe hyperlipidemia of apoE deficiency (5). Evidence in favor of an anti-atherogenic role of apoE also comes from studies showing that low level expression of human apoE-3 in the arterial wall of apoE Ϫ / Ϫ mice was accompanied by decreased growth of lesions without affecting plasma lipids (6), and that the expression of low levels of human apoE-3 in the macrophages of apoE Ϫ / Ϫ mice resulted in decreased atherogenesis independent of a decrease in plasma cholesterol (7). Interestingly, recent studies from our laboratory have shown that retroviral transfer of receptor-binding defective mutant forms of human apoE, such as apoE-2 and apoE-cys142, do not protect apoE null mice against atherosclerosis development, suggesting that the local function of apoE is linked to its ability to bind receptors Abbreviations: BMT, bone marrow transplant; HSPG, heparan sulfate proteoglycans; LDLR, low density lipoprotein receptor; LXR, liver X receptor; TNF ␣ , tumor necrosis factor ␣ .

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