title: Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice.
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.
  
  
  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.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tenn, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Burleigh
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.forename: John A
authors.initials: JA
authors.lastname: Oates
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Shiva
authors.initials: S
authors.lastname: Gautam
authors.forename: Denis
authors.initials: D
authors.lastname: Riendeau
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology / Q000209:etiology* / Q000473:pathology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D016031:Liver Transplantation; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000652:urine; D012333:RNA, Messenger / Q000096:biosynthesis; D011973:Receptors, LDL / Q000235:genetics*; D013450:Sulfones; D013929:Thromboxane B2 / Q000096:biosynthesis
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008055:Lipids; D011453:Prostaglandins; D012333:RNA, Messenger; D011973:Receptors, LDL; D013450:Sulfones; C116926:rofecoxib; D013929:Thromboxane B2; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin