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

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 TXA2 and significantly suppressed levels of macrophage and urinary TXA2 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.