title: High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor.
abstract: 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.
authors.affiliation: Medical Research Center, Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China. yuxycn@hotmail.com
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
authors.forename: Jia-Liang
authors.initials: JL
authors.lastname: Liang
authors.forename: Qiu-Xiong
authors.initials: QX
authors.lastname: Lin
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Lin
authors.forename: Saidan
authors.initials: S
authors.lastname: Zhang
authors.forename: Yangxin
authors.initials: Y
authors.lastname: Li
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose; D002460:Cell Line; D003925:Diabetic Angiopathies / Q000209:etiology*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006943:Hyperglycemia / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017451:Receptors, Somatomedin / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D006657:Histones; D017451:Receptors, Somatomedin; D016159:Tumor Suppressor Protein p53