Pioglitazone May Find a Role in Reducing Restenosis After Arterial Interventions

BACKGROUND: Cytokines induce apoptosis in vascular disease lesions through enhancement of inducible nitric oxide (NO) synthase (iNOS) activation. The thiazolidinediones, novel insulin-sensitizing agents, have been demonstrated to modulate cytokine-induced NO production. We have investigated the role of pioglitazone in the apoptosis of vascular smooth muscle cells (VSMCs) in vitro and developed intimal hyperplasia in vivo. 

METHODS AND RESULTS: Pioglitazone (0.1 to 10 micromol/L) significantly enhanced cytokine-induced expression of iNOS and NO production in a dose-dependent manner in rat VSMCs, but 15-deoxy-Delta(12,14)-prostaglandin J2 (up to 10 micromol/L), a native peroxisome proliferator-activated receptor-gamma ligand, showed no effect. Pioglitazone also significantly enhanced reduction of cell viability, as evidenced by the increase in the number of TUNEL-positive cells. All of these effects of pioglitazone were blocked by treatment with N-monomethyl-L-arginine, an NO synthesis inhibitor. In an in vivo study with a balloon-injured rat carotid artery, neointimal thickness had reached maximum levels at 2 weeks after injury. Then, rats were fed with or without pioglitazone (3 mg. kg(-1). d(-1)) for an additional week. The ratio of intima to media area of carotid artery was significantly decreased by 30%, and the ratio of apoptotic cells in neointima was significantly increased in pioglitazone-treated rats compared with vehicle-treated control rats. 

CONCLUSIONS: Pioglitazone enhanced apoptosis in an NO-dependent manner in cytokine-activated VSMCs and induced significant regression of intimal hyperplasia in balloon-injured rat carotid artery. It appears that pioglitazone is a potent apoptosis inducer in vascular lesions, providing a novel pharmacological strategy to prevent restenosis after vascular intervention. 

Aizawa Y, Kawabe J-I, Hasebe N, et al. Pioglitazone enhances cytokine-induced apoptosis in vascular smooth muscle cells and reduces intimal hyperplasia. Circulation. 2001;104:455-460. 

Last Modified: 2/19/2013