Cyclooxygenase-2 and atherosclerosis.
Cyclooxygenase regulates the production of eicosanoids, which modulate physiologic processes in the vessel wall contributing to atherosclerosis and thrombosis, including platelet aggregation, control of vascular tone, and the local inflammatory response. Cyclooxygenase-1 mediates production of platelet thromboxane A(2), a potent vasoconstrictor and platelet agonist, whereas both cyclooxygenase 1 and 2 contribute to production of endothelial prostacyclin, a vasodilator that inhibits platelet activation. Concerns have been raised that cyclooxygenase-2 inhibitors may increase thrombotic cardiovascular events by disturbing the balance between platelet thromboxane A(2) and endothelial prostacyclin, but this controversial issue will only be resolved by prospective clinical trials. Because cyclooxygenase-2 is upregulated in activated monocyte/macrophages, which play a key role in the pathogenesis of atherosclerosis, we have recently tested the hypothesis that pharmacological inhibition of cyclooxygenase-2 in LDL-receptor deficient mice would reduce early atherosclerosis. After 6 weeks on a Western-type diet, male LDL-receptor deficient mice treated with either rofecoxib (a selective cyclooxygenase-2 inhibitor) or indomethacin (a non-selective cyclooxygenase inhibitor) had significant reductions in atherosclerosis when compared with control mice. Also, LDL-receptor deficient mice null for macrophage cyclooxygenase-2 were generated by fetal liver cell transplantation and developed significantly less atherosclerosis than control LDL-receptor deficient mice transplanted with fetal liver cells wildtype for cyclooxygenase-2, providing genetic evidence in support of a proatherogenic role for macrophage cyclooxygenase-2 expression. These results support the potential of antiinflammatory approaches for the prevention of atherosclerosis and identify cyclooxygenase-2 as a target for intervention.
D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D023903:Coronary Restenosis / Q000378:metabolism; D051546:Cyclooxygenase 2; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism
D007527:Isoenzymes; D008565:Membrane Proteins; D011982:Receptors, Prostaglandin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases