The select cyclooxygenase-2 inhibitor celecoxib reduced the extent of atherosclerosis in apo E-/- mice

Many investigators have suggested that immune activation may trigger the atherosclerotic process. The benefits of aspirin in preventing myocardial infarction have been attributed, in part, to its anti-inflammatory effects. Several reports have documented that cyclooxygenase (COX)-2 is up-regulated in human and mouse atherosclerotic lesions. To clarify the role of COX-2 in atherosclerosis, we conducted a study to test whether the COX-2 inhibitor, celecoxib, prevents the development and progression of the atherosclerotic process. We have used the apo E-/- mouse, a relevant animal model of atherosclerosis that develops fibro-fatty lesions similar to human atherosclerosis. Treatment of 4-wk old apo E-/- mice with a standard rodent no. 5020 diet supplemented with 900 ppm of celecoxib for 16 wk led to an 81% reduction in lesion size. The mean lesion area per section (mean +/- SD) of proximal aorta from the apo E-/- mice fed the diet with celecoxib (33,991 +/- 7863 mu m(2), P < 0.001) was significantly less than that of the untreated apo E-/- mice (183,401 +/- 36,212 mu m(2)). There were no lesions detected in the C57B1/6 mice. Immunohistochemistry of the ileum revealed that there was 80% reduction in staining for intercellular adhesion molecule and 60% reduction in staining for vascular cell adhesion molecule in the celecoxib treated mice. The protective effect of celecoxib was not maintained when the mice were switched after feeding the celecoxib-supplemented diet to the control 5020 diet for an additional 10 wk. These findings demonstrate that selective inhibition of the COX-2 enzyme with celecoxib prevented the development of atherosclerotic lesions in the proximal aortas from apo E-/- mice. One of the possible mechanisms is reduction in expression of the endothelial cell adhesion cell molecules intercellular adhesion molecule and vascular cell adhesion molecule, which plays a key role in the recruitment of inflammatory cells during the early stages of atherogenesis. (c) 2008 Elsevier Inc. All rights reserved.