Troglitazone suppresses intimal formation following balloon injury in insulin-resistant Zucker fatty rats.
Troglitazone, a thiazolidinedione derivative, overcomes insulin resistance through promoting insulin receptor function. However, the effect of the resultant enhancement of insulin action on the regulation of cellular proliferation remains unknown. We investigated the effect of troglitazone on intimal proliferation after balloon injury in insulin-resistant Zucker fatty rats. Troglitazone markedly decreased blood glucose and triglyceride levels at the therapeutic dosage. The area of neointima significantly decreased in treated animals 2 weeks after operation, as compared with the untreated control animals (0.0526 +/- 0.0292 and 0.115 +/- 0.0354 mm2, 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 synthesis in cultured smooth muscle cells (SMCs) derived from non-insulin-resistant rats, to assess whether troglitazone suppresses the proliferation of vascular SMCs independent of metabolic effects. The result showed that troglitazone decreased [methyl-3H]thymidine incorporation into DNA. In conclusion, treatment with troglitazone in Zucker fatty rats resulted in a reduction in neointima formation after balloon injury, and also corrected hypertriglyceridemia and hyperglycemia. In addition, in vitro studies revealed that the anti-proliferative effect of troglitazone stems from its direct action on DNA synthesis rather than any accompanying metabolic changes. Therefore, troglitazone seems to be applicable in preventing atherosclerosis in patients with insulin resistance.
Shinohara
E
E
Second Department of Internal Medicine, Osaka University Medical School, Suita, Japan.
Kihara
S
S
Ouchi
N
N
Funahashi
T
T
Nakamura
T
T
Yamashita
S
S
Kameda-Takemura
K
K
Matsuzawa
Y
Y
D000818:Animals; D002404:Catheterization; D002455:Cell Division; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000293:injuries*; D007333:Insulin Resistance; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D017539:Tunica Intima / Q000166:cytology*
D002839:Chromans; D013844:Thiazoles; D045162:Thiazolidinediones; D004247:DNA; D000077288:Troglitazone