Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-g Activators

Background—Peroxisome proliferator–activated receptor-g (PPARg) is expressed in atherosclerotic plaques and in endothelial cells. The possible effects of PPARg activators on endothelial activation and inflammatory response within the plaque are currently unknown. Methods and Results—We tested the hypothesis that PPARg 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 PPARg agonists troglitazone at 100 mmol/L and 15-deoxy--prostaglandin J2 (15d-PGJ2) at 20 mmol/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 mmol/L 15d-PGJ2 and 20 mmol/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 (236677 versus 177643 macrophages, P50.03); an even more striking inhibition was found at 3200 mg/kg troglitazone (344676 versus 172683 macrophages, P50.005). Conclusions—PPARg 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 PPARg activators, currently used in treatment of type II diabetes, may have beneficial effects in modulating inflammatory response in atherosclerosis. (Circulation. 2000;101:235-238.)