Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-γ activators

Background - Peroxisome proliferator-activated receptor-γ (PPARγ) is expressed in atherosclerotic plaques and in endothelial cells. The possible effects of PPARγ activators on endothelial activation and inflammatory response within the plaque are currently unknown. Methods and Results - We tested the hypothesis that PPARγ 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 PPARγ agonists troglitazone at 100 μmol/L and 1.5-deoxy- (Δ12,14)-prostaglandin J₂ (15d-PGJ2) at 20 μmol/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 μmol/L 15d-PGJ2 and 20 μmol/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 - PPARγ 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 PPARγ activators, currently used in treatment of type II diabetes, may have beneficial effects in modulating inflammatory response in atherosclerosis.