Thiazolidinediones Up-regulate Insulin-like Growth Factor-1 Receptor via a Peroxisome Proliferator-activated Receptor γ-Independent Pathway

There is increasing evidence that thiazolidinediones (TZDs), antidiabetic compounds that are synthetic ligands for the peroxisome proliferator-activated receptor gamma (PPAR gamma), have cardiovascular effects through as yet poorly defined mechanisms. We tested the effect of two TZD class drugs, rosiglitazone and pioglitazone, on human aortic smooth muscle cell (SMC) expression of insulin-like growth factor-1 receptor (IGF-1R). Both TZDs dose dependently up-regulated IGF-1R protein levels (rosiglitazone, 10 mu mol/liter, 67% increase, n = 4, p < 0.01; pioglitazone, 10 mu mol/liter, 41% increase, n = 4, p < 0.01) and increased IGF-1R signaling activity (36% increase in Akt phosphorylation). However, the endogenous PPAR gamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2), dose dependently reduced IGF-1R (10 mu mol/liter, 80% decrease, n = 4, p < 0.01), and overexpression of PPAR gamma using an adenovirus likewise reduced IGF-1R (50% decrease versus SMC infected with control adenovirus), suggesting a PPAR gamma-independent action of TZDs. All three PPAR gamma ligands (rosiglitazone, pioglitazone, and 15-deoxy-Delta(12,14)-prostaglandin J2), however, did not change IGF-1R mRNA levels, indicating that their effects were posttranscriptional. Use of bicistronic constructs revealed that TZD induction of IGF-1R translation occurred via internal ribosomal entry. To examine the potential physiological relevance of TZD up-regulation of IGF-1R, we determined the effect of rosiglitazone on oxidized LDL (oxLDL)-induced apoptosis. 20 mu mol/liter of rosiglitazone reduced oxidized LDL-induced apoptosis by 40% and neutralizing antibody to IGF-1R (alpha IR3) counteracted this rescue, suggesting the rosiglitazone survival effect was, at least in part, mediated by IGF-1R. In conclusion, TZDs markedly up-regulate SMC IGF-1R expression and signaling, likely via a PPAR gamma-independent mechanism. This novel action of TZDs may play an important role in their cardiovascular effects.