Cyclooxygenase-1 Deficiency in Bone Marrow Cells Increases Early Atherosclerosis in Apolipoprotein E– and Low-Density Lipoprotein Receptor–Null Mice

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Abstract
Background— Cyclooxygenase-1 (COX-1) has been implicated in the pathogenesis of atherothrombosis and is expressed by the major cell types of atherosclerotic lesions. COX-1–mediated platelet thromboxane (TX) production has been proposed to promote both early atherosclerosis and thrombosis. Here, we examined the impact of COX-1 deficiency in bone marrow–derived cells on early atherogenesis in the mouse. Methods and Results— LDL receptor (LDLR) −/− and apolipoprotein E (apoE) −/− recipient mice were lethally irradiated and transplanted with COX-1 −/− bone marrow. Mice reconstituted with COX-1 −/− marrow had nearly complete (99.7%) loss of platelet TXA 2 and significantly suppressed levels of macrophage and urinary TXA 2 metabolites. Serum lipid levels and lipoprotein distributions did not differ between recipients reconstituted with COX-1 +/+ and COX-1 −/− marrow. Surprisingly, the extent of atherosclerotic lesions in both LDLR −/− and apoE −/− mice reconstituted with COX-1 −/− marrow was increased significantly compared with control mice transplanted with COX-1 +/+ marrow. Peritoneal macrophages isolated from LDLR −/− mice reconstituted with COX-1 −/− marrow had increased lipopolysaccharide-induced levels of COX-2 mRNA and protein expression. Fetal liver cell transplantation studies revealed a 30% increase in atherosclerosis in COX-1 −/− →LDLR −/− mice compared with COX-1 +/+ →LDLR −/− mice, whereas the extent of atherosclerosis was unchanged in COX-1 −/− /COX-2 −/− →LDLR −/− mice. Conclusions— COX-1 deficiency in bone marrow–derived cells worsens early atherosclerosis in apoE −/− and LDLR −/− mice despite virtual elimination of platelet TX production. These data demonstrate that platelet TX production does not aggravate early atherosclerotic lesion formation and that upregulation of COX-2 expression in COX-1 −/− macrophages is proatherogenic.