Abstract 495: A Novel Antiatherosclerotic Effect of the Thiazolidinedione Class of Peroxisome Proliferator-Activated Receptor γ Ligands: Upregulation of Vascular Smooth Muscle Insulin-Like Growth Factor-1 Receptor Expression and Signaling
There is increasing evidence that thiazolidinediones (TZDs), antidiabetic componds that are synthetic ligands for peroxisome proliferator-activated receptor γ (PPARγ), have antiathero-sclerotic effects through as yet poorly defined mechanisms. We have recently shown that the proatherogenic lipoprotein, oxidized LDL (OxLDL), downregulates vascular smooth muscle cell (SMC) insulin-like growth factor (IGF-1) and IGF-1 receptor (IGF-1R) in human atherosclerotic plaques and that IGF-1 infusion reduces atherosclerosis progression in the ApoE-/- model of atherosclerosis via pleiotropic effects including stimulation of anti-inflammatory and anti-apoptotic pathways. To explore potential mechanisms for the vasculoprotective effects of TZDs, we exposed human aortic SMC to 0 –10 μM rosiglitazone (R) or pioglitazone (P) for 0 –24h and assessed IGF-1R expression by western blot analysis. Both TZDs dose-dependently upregulated IGF-1R protein levels (R, 10μM, 67% increase, n=4, p<0.01, P, 10μM, 41% increase, n=4, p<0.01) and increased SMC survival. However, the endogenous PPARγ ligand, 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), dose-dependently reduced IGF-1R (10 μM, 80% decrease, n=4, p<0.01) and increased SMC apoptotic rates. Overexpression of PPARγ using an adenovirus likewise reduced IGF-1R (50% decrease vs SMC infected with control adenovirus encoding green fluorescent protein) and incubation with 10μM R counteracted the PPARγ induced decrease in IGF-1R, resulting in partial rescue of IGF-1R expression. Conversely, the PPARγ antagonist, prostaglandin F2α dose-dependently (0- 1 μM) increased IGF-1R expression (maximal 3.8 fold increase at 1 μM, p<0.01). The differential regulation of IGF-1R by TZDs and PGJ2 was reflected in corresponding changes in IGF-1R signaling as assessed by IGF-1 induced Akt phosphorylation (e.g., PGJ2, 10 μM, 80% decrease, n=3, P<0.01). In summary, TZDs markedly upregulate SMC IGF-1R expression and signaling, likely via a PPARγ independent mechanism, providing a potential novel mechanism for the atheroprotective effects of these compounds.