Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice
Michael E Burleigh1, Vladimir R Babaev, John A Oates
1Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tenn, USA.
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-PGF1alpha. 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.
Insights
Selective cyclooxygenase-2 (COX-2) inhibition reduces early atherosclerosis in mice. Macrophage COX-2 expression also contributes to the development of atherosclerosis, supporting anti-inflammatory strategies.
Area of Science:
- Cardiovascular Research
- Inflammation and Immunology
- Pharmacology
Background:
- Atherosclerosis is characterized by inflammation.
- Cyclooxygenase-2 (COX-2) is present in atherosclerotic lesions and promotes inflammation.
Purpose of the Study:
- To investigate if selective COX-2 inhibition reduces early lesion formation in LDL receptor-deficient (LDLR-/-) mice.
- To determine if macrophage COX-2 expression contributes to atherogenesis in LDLR-/- mice.
Main Methods:
- Male LDLR-/- mice were treated with rofecoxib or indomethacin (selective COX-2 inhibitors) or underwent fetal liver cell transplantation to generate mice lacking macrophage COX-2.
- Mice were fed a Western diet for 6-8 weeks.
- Atherosclerosis was assessed in the aorta, and serum lipids were measured.
Main Results:
- Rofecoxib and indomethacin treatments significantly reduced atherosclerosis in the aorta.
- Mice lacking macrophage COX-2 expression (COX-2-/- --> LDLR-/-) developed significantly less atherosclerosis compared to controls.
- Rofecoxib did not affect platelet thromboxane production but reduced urinary prostacyclin metabolite levels.
- Serum lipid levels did not differ significantly between groups in either study.
Conclusions:
- Pharmacological and genetic evidence demonstrate that COX-2 promotes early atherosclerotic lesion formation in LDLR-/- mice.
- These findings support the potential of anti-inflammatory approaches for atherosclerosis prevention.
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