Circulation. 2002;105:1816-1823
Published online before print April 8, 2002, doi: 10.1161/01.CIR.0000014927.74465.7F
Published online before print April 8, 2002, doi: 10.1161/01.CIR.0000014927.74465.7F
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(Circulation. 2002;105:1816.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Cyclooxygenase-2 Promotes Early Atherosclerotic Lesion Formation in LDL Receptor–Deficient Mice
From the Departments of Pharmacology (M.E.B., J.A.O., J.D.M., M.F.L.), Medicine (V.R.B., J.A.O., R.C.H., J.D.M., S.F., M.F.L.), Preventive Medicine (S.G.), Biochemistry (L.J.M.), and Pathology (S.F.), Vanderbilt University Medical Center, Nashville, Tenn; and Merck Frosst (D.R.), Centre for Therapeutic Research, Kirkland, Quebec.
*These authors contributed equally to this study.
This article originally appeared Online on April 8, 2002 (Circulation. 2002;105:r53–r60).Correspondence to Dr MacRae F. Linton or Dr Sergio Fazio, Cardiovascular Medicine, Vanderbilt University School of Medicine, 383 Preston Research Building, Nashville, TN 37232-6300. E-mail macrae.linton{at}mcmail.vanderbilt.edu or sergio.fazio@mcmail.vanderbuilt.edu
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-PGF1
. 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. (Circulation. 2002;105:1816-1823.)
Key Words: atherosclerosis • inflammation • mice • macrophage • transplantation
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