TROGLITAZONE SUPPRESSES INTIMAL FORMATION FOLLOWING BALLOON INJURY ININSULIN-RESISTANT ZUCKER FATTY RATS

Troglitazone, a thiazolidinedione derivative, overcomes insulin resist ance through promoting insulin receptor function. However, the effect of the resultant enhancement of insulin action on the regulation of ce llular proliferation remains unknown. We investigated the effect of tr oglitazone on intimal proliferation after balloon injury in insulin-re sistant Zucker fatty rats. Troglitazone markedly decreased blood gluco se and triglyceride levels at the therapeutic dosage. The area of neoi ntima significantly decreased in treated animals 2 weeks after operati on, as compared with the untreated control animals (0.0526 +/- 0.0292 and 0.115 +/- 0.0354 mm(2), respectively). The ratio of neointimal to medial area in treated rats (0.75 +/- 0.26) decreased by as much as 53 % compared with untreated rats (1.40 +/- 0.05). We next examined DNA s ynthesis in cultured smooth muscle cells (SMCs) derived from non-insul in-resistant rats, to assess whether troglitazone suppresses the proli feration of vascular SMCs independent of metabolic effects. The result showed that troglitazone decreased [methyl-H-3]thymidine incorporatio n into DNA. In conclusion, treatment with troglitazone in Zucker fatty rats resulted in a reduction in neointima formation after balloon inj ury, and also corrected hypertriglyceridemia and hyperglycemia. In add ition, in vitro studies revealed that the anti-proliferative effect of troglitazone stems from its direct action on DNA synthesis rather tha n any accompanying metabolic changes. Therefore, troglitazone seems to be applicable in preventing atherosclerosis in patients with insulin resistance. (C) 1998 Elsevier Science Ireland Ltd.