Journal
CIRCULATION
Volume 101, Issue 3, Pages 235-238Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.CIR.101.3.235
Keywords
cell adhesion molecules; receptors; atherosclerosis
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Background-Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is expressed in atherosclerotic plaques and in endothelial cells. The possible effects of PPAR gamma activators on endothelial activation and inflammatory response within the plaque are currently unknown. Methods and Results-We tested the hypothesis that PPAR gamma activators inhibit vascular cell adhesion molecule (VCAM-1) and intercellular adhesion molecule (ICAM-1) expression in cultured endothelial cells (evaluated by flow cytometry) and homing of monocyte/macrophages to atherosclerotic plaques in vivo. In endothelial cells, the PPAR gamma agonists troglitazone at 100 mu mol/L and 15-deoxy-(Delta 12,14)-prostaglandin J(2) (15d-PGJ2) at 20 mu mol/L markedly attenuated the tumor necrosis factor-induced expression of VCAM-1 and ICAM-1. A significant inhibition of VCAM-1 expression was also evident at 5 and 10 mu mol/L 15d-PGJ2 and 20 mu mol/L troglitazone. Expression of E-selectin and PECAM-1 was not altered. To confirm the biological relevance of these results, we assessed the effects of troglitazone on monocyte/macrophage homing to atherosclerotic plaques in apoE-deficient mice. A 7-day treatment with troglitazone (400 mg/kg) significantly reduced monocyte/macrophage homing to atherosclerotic plaques (236+/-77 versus 177+/-43 macrophages, P=0.03); an even more striking inhibition was found at 3200 mg/kg troglitazone (344+/-76 versus 172+/-83 macrophages, P=0.005). Conclusions-PPAR gamma activators inhibit expression of VCAM-1 and ICAM-1 in activated endothelial cells and significantly reduce monocyte/macrophage homing to atherosclerotic plaques. These findings suggest that PPAR gamma activators, currently used in treatment of type II diabetes, may have beneficial effects in modulating inflammatory response in atherosclerosis.
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