Abstract 1372: High Levels of Glucose Induce Apoptosis in Cardiomyocyte via Epigenetic Regulation of the Insulin-Like Growth Factor Receptor
Diabetic hyperglycemia result in cardiovascular complications, but the mechanism by which high levels of glucose (HG) causes diabetic cardiomyopathy are not known. We investigated the role that the insulin-like growth factor (IGF-1) signaling pathway plays in the development of diabetic cardiomyopathy. Incubating H9C2 rat ventricular cells in high glucose (25 mM) resulted in decreased IGF-1 receptor (IGF-1R) mRNA levels (3.6±0.6 fold at 48 h, p<0.02, assessed by real-time PCR) and IGF-1R protein (2.8±0.4 fold at 72 h, p<0.05, assessed by Western blot) when compared with myocytes incubated in normal glucose (5 mM). HG (25 mM, 96 h) also induced apoptosis of H9C2 cells as assessed by Death ELISA (O.D. value=0.46±0.07 in glucose group vs. 0.14±0.04 in control, p<0.02). The effects of HG on reduced expression of IGF-1R and increased apoptosis were blocked by silencing p53 with small interference RNA but not by non-targeting scrambled siRNA. Moreover, HG negatively regulated IGF-1R promoter activity as determined by ChIP analysis, which was dependent on p53 since siRNA-p53 attenuated the effects of HG on IGF-1R promoter activity. HG also increased the association of p53 with histone deacetylase 1 (HDAC1), and decreased the association of acetylated histone-4 with the IGF-1R promoter. Furthermore, trichostatin A, a specific HDAC inhibitor, relieved the repression of IGF-1R and prevented apoptosis of myocytes following HG state. These results suggest that HG-induced repression of IGF-1R is mediated by the association of p53 with the IGF-1R promoter, and by the subsequent enhanced recruitment of chromatin-modifying proteins, such as HDAC1, to the IGF-1R promoter-p53 complex. In conclusion, our data demonstrate that high glucose exposure decreases expression of IGF-1R and decreases the association of acetylated histone-4 with the IGF-1R promoter, and suggest that enhancing acetylation of histone 4 and IGF-1R expression may be a useful strategy to prevent diabetic cardiomyopathy.