title: Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice.
abstract: Cyclooxygenase (COX) 2 is expressed in atherosclerotic lesions. We have previously reported that selective inhibition of COX-2 reduces early atherosclerosis in LDLR deficient mice. To examine the role of COX-2 in atherosclerosis in other mouse models, we studied the effects of selective COX-2 inhibition (by rofecoxib and NS-398) and nonselective COX inhibition (by indomethacin) on early atherosclerotic lesion formation in apolipoprotein E-deficient (apoE(-/-)) mice. Selective COX-2 and nonselective COX inhibition reduced atherosclerosis in female apoE(-/-) mice by 35-38% and 38-51% in the proximal and en face aortas, respectively. Next we investigated the role of macrophage COX-2 by transplanting COX-2(-/-) fetal liver cells into C57BL/6 mice and challenging the mice with an atherogenic diet. Genetic deletion of COX-2 from hematopoietic cells reduced atherosclerosis by 51%. In addition, LPS activated COX-2(-/-) macrophages had decreased expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNFalpha). The results demonstrate that selective inhibition of COX-2 and elimination of COX-2 from macrophages significantly reduces early atherosclerotic lesion formation in apoE-deficient and C57BL/6 mice. These results are compatible with COX-2 expression by macrophages having a proatherogenic role, and support the potential of anti-inflammatory therapeutic approaches for atherosclerosis.
authors.affiliation: Department of Pharmacology, 383 Preston Research Building, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Burleigh
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Yancey
authors.forename: Amy S
authors.initials: AS
authors.lastname: Major
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McCaleb
authors.forename: John A
authors.initials: JA
authors.lastname: Oates
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; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016031:Liver Transplantation; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D018932:Chemokine CCL2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D013449:Sulfonamides; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C116926:rofecoxib; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin