High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor

• Published in: Experimental cell research 2010-10, Vol.316 (17), p.2903-2909
• Main Authors: Yu, Xi-Yong, Geng, Yong-Jian, Liang, Jia-Liang, Lin, Qiu-Xiong, Lin, Shu-Guang, Zhang, Saidan, Li, Yangxin
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Apoptosis; Blood Glucose; Cardiovascular disease; Cell Line; Cellular biology; Diabetes; Diabetic Angiopathies - etiology; Epigenesis, Genetic; Epigenetic regulation; Glucose; Histones - metabolism; Hyperglycemia - pathology; IGF-1 receptor; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; p53; Promoter Regions, Genetic; Proteins; Rats; Receptors, Somatomedin - genetics; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2010.07.004

Diabetic hyperglycemia result in cardiovascular complications, but the mechanisms by which high levels of glucose (HG) cause diabetic cardiomyopathy are not known. We investigate whether HG-induced repression of insulin-like growth factor 1 receptor (IGF-1R) mediated by epigenetic modifications is one potential mechanism. We found that HG resulted in decreased IGF-1 receptor (IGF-1R) mRNA levels, and IGF-1R protein when compared with H9C2 rat cardiomyocyte cells incubated in normal glucose. HG also induced apoptosis of H9C2 cells. 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, HDAC inhibitor relieved the repression of IGF-1R 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 HG decreases expression of IGF-1R and decreases the association of acetylated histone-4 with the IGF-1R promoter. These studies may help delineate the complex pathways regulating diabetic cardiomyopathy, and have implications for the development of novel therapeutic strategies to prevent diabetic cardiomyopathy by epigenetic regulation of IGF-1R.