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

Research output: Contribution to journalArticlepeer-review

281 Scopus citations


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
Issue number15
StatePublished - Apr 16 2002
Externally publishedYes


  • Atherosclerosis
  • Inflammation
  • Macrophage
  • Mice
  • Transplantation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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