Peroxisome proliferator-activated receptor gamma down-regulates receptor for advanced glycation end products and inhibits smooth muscle cell proliferation in a diabetic and nondiabetic rat carotid artery injury model.

Diabetes is associated with an increase in circulating advanced glycosylation end products (AGEs) and the increased expression of the receptor for AGEs (RAGE). Inhibition of AGE/RAGE binding through the administration of soluble RAGE (sRAGE) has been shown to decrease neointimal hyperplasia. Peroxisome proliferator-activated receptor gamma (PPARgamma), which inhibits neointimal hyperplasia, has been shown to decrease RAGE expression in cultured endothelial cells. We hypothesized that PPARgamma agonists inhibit neointimal hyperplasia via down-regulation of RAGE in vivo. Pretreatment of rat aortic smooth muscle cells (SMCs) with PPARgamma agonist rosiglitazone significantly down-regulated RAGE expression and inhibited SMC proliferation in response to the RAGE agonist S100/calgranulins. In vivo studies showed that rosiglitazone decreased RAGE expression and SMC proliferation at 7 days following carotid arterial injury in both diabetic and nondiabetic rats. At 21 days following injury, neointimal formation was significantly decreased in both diabetic and nondiabetic animals that received rosiglitazone. To determine whether inhibition of neointimal formation by PPARgamma activation could fully be accounted for by its down-regulation of RAGE, we compared the results obtained in animals treated with sRAGE, PPARgamma activator, and sRAGE + PPARgamma activator. Consistent with PPARgamma working through its effects on RAGE, we found that the addition of PPARgamma activator to sRAGE did not result in any further decrease in neointimal formation. These data demonstrate for the first time that PPARgamma agonists inhibit RAGE expression at sites of arterial injury and suggest that down-regulation of RAGE by the PPARgamma activation inhibits neointimal formation in response to arterial injury.