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(Circulation. 2006;113:108-117.)
© 2006 American Heart Association, Inc.

Vascular Medicine

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

Vladimir R. Babaev, PhD; Lei Ding, BA; Jeff Reese, MD; Jason D. Morrow, MD; Matthew D. Breyer, MD; Sudhansu K. Dey, PhD; Sergio Fazio, MD, PhD; MacRae F. Linton, MD

From the Department of Medicine (V.R.B., L.D., S.F., M.F.L.), Pediatrics (J.R., S.K.D.), Molecular Physiology & Biophysics (J.D.M.), Nephrology (M.D.B.), Pathology (S.F.), and Pharmacology (M.F.L.) of Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Vladimir Babaev, Sergio Fazio, or MacRae F. Linton, Department of Cardiovascular Medicine, Vanderbilt University School of Medicine, 312 PRB, 2220 Pierce Ave, Nashville, TN 37232-6300. E-mail vladimir.babaev{at}vanderbilt.edu, sergio.fazio@vanderbilt.edu, or macrae.linton@vanderbilt.edu

Received June 11, 2005; de novo received September 28, 2005; accepted October 21, 2005.

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.

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