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.