Cyclooxygenase-1 deficiency in bone marrow cells increases early atherosclerosis in apolipoprotein E- and low-density lipoprotein receptor-null mice

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

    Research output: Contribution to journalArticle

    28 Scopus citations

    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 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→LDLRmice compared with COX-1→LDLRmice, whereas the extent of atherosclerosis was unchanged in COX-1/COX- 2→LDLRmice. 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.

    Original languageEnglish (US)
    Pages (from-to)108-117
    Number of pages10
    JournalCirculation
    Volume113
    Issue number1
    DOIs
    StatePublished - Jan 1 2006

    Keywords

    • Cyclooxygenase
    • Macrophages
    • Platelets
    • Prostaglandins
    • Thromboxane

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

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