Troglitazone (TGZ) is an antidiabetic agent of the thiazolidinedione (TZD) class that potentiates insulin action. In addition to its effects on insulin action, TGZ has an antiproliferative effect on vascular smooth muscle cells (VSMCs), of which proliferation is a prominent feature of retenosis after balloon injury, as well as atherosclerosis. Therefore, we investigated the effects of TGZ on intimal formation and blood flow after balloon injury in insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats to see whether the decrease in insulin resistance could minimize VSMC proliferation and could maintain blood flow. OLETF rats, an animal model of type 2 diabetes, develop spontaneous hyperglycemia after the age of 24 weeks. Balloon injury was applied to the left common carotid arteries of the rats with a 2F Fogarty catheter. Two weeks after the balloon injury, blood flow velocity was measured with Doppler ultrasonography, and histomorphometric analyses of the common carotid arteries were performed. The neointimal formation caused by VSMC proliferation was inhibited by TGZ treatment by as much as 80% (0.197 +/- 0.013 mm(2) v 0.157 +/- 0.011 mm(2), P <.05). The ratio of neointimal to medial area also decreased by 22% with TGZ treatment (1.651 +/- 0.148 v 1.292 +/- 0.083, P <.05). These effects of TGZ in OLETF rats were accompanied by alterations in plasma insulin, triglyceride, and total cholesterol levels. To look into the relationship between VSMC proliferation and hyperinsulinemia, we used a [(3)H]-thymidine incorporation assay to investigate the effects of TGZ on VSMC proliferation. Insulin (at a concentration of 17.3 nmol/L) significantly stimulated DNA synthesis (236.6% +/- 7.4%, P <.001), and TGZ significantly inhibited the insulin-induced DNA synthesis in VSMCs (106.43% +/- 4.23%, P <.001) in a dose-dependent manner. In balloon-injured arteries of the untreated group, systolic blood flow velocity decreased by 61% compared with uninjured arteries (P <.05). However, there was no significant difference in systolic blood flow velocity between injured and uninjured arteries in the treated group (0.906 +/- 0.043 v 0.991 +/- 0.066 meters per second [m/s], P = not significant [NS]). The systolic blood flow of injured arteries was improved by 143% in the treated group (P <.01). These data suggest that TGZ is a potent inhibitor of VSMC proliferation both in vivo and in vitro through a direct effect on VSMCs, and that TZDs might be very useful in the treatment and prevention of restenosis after balloon injury.
Copyright 2002, Elsevier Science (USA). All rights reserved.