Thiazolidinedione regulation of smooth muscle cell proliferation

Vascular smooth muscle cells (VSMCs) in the media of adult arteries are normally quiescent, proliferate at low frequency, and are arrested in the G0/G1 phase of the cell cycle. Proliferation of VSMCs occurs in response to arterial injury and plays a crucial role in the atherosclerotic process and in the pathogenesis of restenosis. Patients with type 2 diabetes mellitus are at increased risk for postangioplasty restenosis, which results from excessive intimal hyperplasia. Insulin sensitizers of the thiazolidinedione (TZD) class inhibit growth of VSMCs by attenuating the activity of important cell-cycle regulators. The TZDs inhibit progression from G1 to S phase in the cell cycle by blocking growth factor–induced phosphorylation of retinoblastoma tumor suppressor protein (Rb). In animal models of restenosis, TZDs inhibit intimal hyperplasia after mechanical injury in both insulin-sensitive and insulin-resistant vessels. Preliminary clinical studies using troglitazone demonstrate less intimal hyperplasia with this TZD after implantation of coronary stents in individuals with type 2 diabetes. Further large trials are needed to confirm that treatment with a TZD can protect against postangioplasty restenosis.