High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor
High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor
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高水平葡萄糖通过胰岛素样生长因子受体的表观遗传调控诱导心肌细胞凋亡
DOI：
10.1016/j.yexcr.2010.07.004
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发表时间：
2010-10-15
影响因子：
3.7
通讯作者：
Li, Yangxin
中科院分区：
文献类型：
--
作者：
Yu, Xi-Yong;Geng, Yong-Jian;Li, Yangxin
糖尿病高血糖可导致心血管并发症，但高血糖引起糖尿病心肌病的机制尚不清楚。我们研究了由表观遗传修饰介导的HG诱导的胰岛素样生长因子1受体（IGF-1 R）抑制是否是一种潜在机制。我们发现，与正常葡萄糖孵育的H9 C2大鼠心肌细胞相比，HG导致IGF-1受体（IGF-1 R）mRNA水平和IGF-1 R蛋白水平降低。HG还可诱导H9 C2细胞凋亡。HG对IGF-1 R表达减少和凋亡增加的影响可被小干扰RNA沉默p53所阻断，但不能被非靶向的scrambled siRNA所阻断。此外，HG负调控IGF-1 R启动子活性，如通过ChIP分析所确定的，这是依赖于p53，因为siRNA-p53减弱HG对IGF-1 R启动子活性的影响。HG还增加了p53与组蛋白去乙酰化酶1（HDAC 1）的结合，并减少了乙酰化组蛋白4与IGF-1 R启动子的结合。HDAC抑制剂可解除高糖状态对IGF-1 R的抑制。这些结果表明，HG诱导的IGF-1 R的抑制是通过p53与IGF-1 R启动子的结合以及随后增强的染色质修饰蛋白（如HDAC 1）向IGF-1 R启动子p53复合物的募集来介导的。总之，我们的数据表明，HG降低IGF-1 R的表达，并减少与IGF-1 R启动子的乙酰化组蛋白-4的协会。这些研究可能有助于描述调节糖尿病心肌病的复杂途径，并对开发新的治疗策略以通过表观遗传调节IGF-1 R来预防糖尿病心肌病具有意义。(C)2010年爱思唯尔公司All rights reserved.
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 promoterp53 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. (C) 2010 Elsevier Inc. All rights reserved.