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 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.