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-PGF1α. 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 language | English (US) |
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Pages (from-to) | 1816-1823 |
Number of pages | 8 |
Journal | Circulation |
Volume | 105 |
Issue number | 15 |
DOIs | |
State | Published - Apr 16 2002 |
Externally published | Yes |
Keywords
- Atherosclerosis
- Inflammation
- Macrophage
- Mice
- Transplantation
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)