Troglitazone stimulates repair of the endothelium and inhibits neointimal formation in denuded rat aorta

Objective - Vascular endothelium is emerging as a therapeutic target for atherosclerotic macrovascular disease in diabetes using oral hypoglycemic agents with pleiotropic actions. We have addressed whether the thiazolidinedione troglitazone has effects on the endothelial cell response to injury in rat aorta and its interaction with the growth response of underlying vascular smooth muscle. Methods and Results - Repair of rat aorta after balloon catheter injury in troglitazone-treated ( 400 mg/kg per day by mouth) rats showed early acceleration of reendothelialization and late reduction in neointima formation. Complementary in vitro studies showed that troglitazone dose-dependently inhibited migration and proliferation of cultured macrovascular endothelial and vascular smooth muscle cells in low-glucose (5 mmol/L) and high-glucose (25 mmol/L) media. However, in endothelial cells, the inhibitory response at low (<3 μmol/L) troglitazone concentrations resulted from direct inhibition of proliferation, whereas inhibition at higher (10 μmol/L) concentrations was secondary to apoptosis and necrosis. Additional studies indicated a concentration-specific activity of troglitazone to protect endothelial cells from apoptosis. Conclusions - Troglitazone had effects consistent with maintenance of vascular integrity and protection against mechanisms of atherosclerosis and restenosis, which may arise from a concentration-specific effect to reduce high rates of apoptosis occurring in cultured cells and repairing vessels.