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

Abstract

There is increasing evidence that thiazolidinediones (TZDs), antidiabetic compounds that are synthetic ligands for the peroxisome proliferator-activated receptor ␥ (PPAR␥), 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 mol/liter, 67% increase, n ‫؍‬ 4, p < 0.01; pioglitazone, 10 mol/liter, 41% increase, n ‫؍‬ 4, p < 0.01) and increased IGF-1R signaling activity (36% increase in Akt phosphorylation). However, the endogenous PPAR␥ ligand, 15-deoxy-⌬ 12,14 -prostaglandin J 2 , dose dependently reduced IGF-1R (10 mol/liter, 80% decrease, n ‫؍‬ 4, p < 0.01), and overexpression of PPAR␥ using an adenovirus likewise reduced IGF-1R (50% decrease versus SMC infected with control adenovirus), suggesting a PPAR␥-independent action of TZDs. Thiazolidinediones (TZDs) 2 are insulin-sensitizing drugs used in patients with type 2 diabetes mellitus. Over the past decade, it has been suggested that TZDs could have anti-atherosclerotic effects (1-4), although human studies thus far have not been conclusive with regard to potential benefits (5-7), and one meta-analysis has suggested that rosiglitazone increased the risk of myocardial infarction (8). PPAR␥ agonists including TZDs have been found to reduce atherosclerosis in rodent models such as LDL receptor-null mice and apolipoprotein E-deficient mice (9 -12). TZDs inhibit proliferation and migration of cultured vascular smooth muscle cells (SMCs), which may contribute to their potential beneficial effect on atherogenesis (13-15).Insulin-like growth factor-1 (IGF-1), a growth factor found in the circulation and also produced locally in multiple tissues including the vasculature, has pleiotropic effects on vascular cells including SMCs (reviewed in Refs. 16 and 17). For instance, IGF-1 is a mitogen for vascular SMCs and could be involved in the restenotic process after mechanical vascular injury (18,19). Contrary to its mitogenic effect, it has also been reported that IGF-1 signaling is important for maintenance of the differentiated SMC phenotype (20, 21). IGF-1 is a potent survival factor for vascular SMCs. Thus, we have previously reported that oxidized low density lipoprotein (oxLDL), a highly pro-atherogenic lipoprotein present in circulation and in atherosclerotic plaques (22, 23), down-regulates IGF-1 in vascular cells (16,24), and overexpression of IGF-1 receptor (IGF-1R) prevents oxLDL-induced apoptosis of vascular cells (25). Intriguingly, IGF-1 and IGF-1R expression are reduced in areas of advanced human plaque staining positive for oxLDL (26,27), indicating a potential association between reduced IGF-1 function and the acellular phenotype of advanced plaques. Collectively, our studies suggest that IGF-1 serves as a survival factor for vascular SMCs, preventing SMC loss from atherosclerotic ...

Chemical Proteomics-Based Analysis of Off-Target Binding Profiles for Rosiglitazone and Pioglitazone: Clues for Assessing Potential for Cardiotoxicity

“…Receptor-independent actions of rosiglitazone and pioglitazone have been reported in previous literature 18, 31 and this study has identified numerous off-target interacting proteins involved in mitochondrial function, lipid/fatty acid metabolism, and glycolysis/gluconeogenesis regulation (Tables 1–4 and Supplemental Table 1). Previous literature has indicated that PPARγ antagonists and transcriptional/translational inhibitors do not abolish TZD effects 18, 32 , suggesting there are additional effects contributing to increasing insulin sensitivity.…”

Orally efficacious novel small molecule 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-d-glucopyranose selectively and potently stimulates insulin receptor and alleviates diabetes

“…There is evidence showing that using insulin and insulin analogs to treat diabetes increases cancer rates as they may also activate IGF1R signaling (Gunter et al 2009, Hemkens et al 2009, Wilson 2011). The problem is compounded by a nationwide cohort study showing that most glucose-lowering antidiabetic medications, including thiazolidinediones and sulfonylureas, increase cancer risk (Higashi et al 2010, Andersson et al 2012. Therefore, efforts are needed to find new glucose-lowering agents with low carcinogenicity and other side effects.…”

“…For instance, cDNA microarray analysis of NIH-3T3 cells indicated that more than half of the genes upregulated by IGF1R activation are associated with mitogenesis and differentiation, whereas none of the genes specifically upregulated by IR activation are associated with these processes, suggesting that IGF1R activation is more mitogenic than IR activation (Dupont et al 2001b). Indeed, IGF1R activation has been found to be intimately associated with cancer development (Higashi et al 2010, Lewis et al 2010, Wu et al 2011, Huang et al 2012, Ma et al 2012. There is evidence showing that using insulin and insulin analogs to treat diabetes increases cancer rates as they may also activate IGF1R signaling (Gunter et al 2009, Hemkens et al 2009, Wilson 2011).…”

“…6Cl-TGQ did not activate IGF1R signaling or stimulate cancer growth IGF1R is highly homologous with IR and intimately involved in cancer progression (Higashi et al 2010, Lewis et al 2010, Wu et al 2011, Huang et al 2012, Ma et al 2012. A serious problem for IR signaling activators is that they might not distinguish IGF1R from IR, activating IGF1R and increasing cancer rates (Gunter et al 2009, Hemkens et al 2009, Wilson 2011.…”

“…Both IR and IGF1R signaling pathways consist of two major branches, the PI3K-Akt pathway and the MAPK pathway. Any IR signaling activator also tends to activate oncogenic IGF1R signaling (Higashi et al 2010, Lewis et al 2010, Wu et al 2011, Huang et al 2012, Ma et al 2012. Few agents are known to selectively activate IR signaling without triggering IGF1R signaling.…”