Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice.

Burleigh ME, Babaev VR, Yancey PG, Major AS, McCaleb JL, Oates JA, Morrow JD, Fazio S, Linton MF
J Mol Cell Cardiol. 2005 39 (3): 443-52

PMID: 16040051 · DOI:10.1016/j.yjmcc.2005.06.011

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.

MeSH Terms (26)

Animals Aorta Apolipoproteins E Arteriosclerosis Cells, Cultured Chemokine CCL2 Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Female Immunohistochemistry Indomethacin Lactones Lipopolysaccharides Liver Transplantation Macrophages Male Mice Mice, Inbred C57BL Mice, Knockout Nitrobenzenes Prostaglandin-Endoperoxide Synthases Sulfonamides Sulfones Transplantation, Heterologous Tumor Necrosis Factor-alpha

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