Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice

Michael E. Burleigh, Vladimir R. Babaev, John A. Oates, Raymond C. Harris, Shiva Gautam, Denis Riendeau, Lawrence J. Marnett, Jason D. Morrow, Sergio Fazio, MacRae F. Linton

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    269 Scopus citations

    Abstract

    Background - Atherosclerosis has features of an inflammatory disease. Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor-deficient (LDLR-/-) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR-/- mice. Methods and Results - Treatment of male LDLR-/- mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in the aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1-mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF. Fetal liver cell transplantation was used to generate LDLR-/- mice null for expression of the COX-2 gene by macrophages. After 8 weeks on the Western diet, COX-2-/-→LDLR-/- mice developed significantly less (33% to 39%) atherosclerosis than control COX-2+/+→LDLR-/- mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups. Conclusions - The present studies provide strong pharmacological and genetic evidence that COX-2 promotes early atherosclerotic lesion formation in LDLR-/- mice in vivo. These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis.

    Original languageEnglish (US)
    Pages (from-to)1816-1823
    Number of pages8
    JournalCirculation
    Volume105
    Issue number15
    DOIs
    StatePublished - Apr 16 2002

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    Keywords

    • Atherosclerosis
    • Inflammation
    • Macrophage
    • Mice
    • Transplantation

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

    Cite this

    Burleigh, M. E., Babaev, V. R., Oates, J. A., Harris, R. C., Gautam, S., Riendeau, D., Marnett, L. J., Morrow, J. D., Fazio, S., & Linton, M. F. (2002). Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation, 105(15), 1816-1823. https://doi.org/10.1161/01.CIR.0000014927.74465.7F