风湿性心脏瓣膜病中的DNA甲基化失调

DNA methylation dysregulations in rheumatic heart valve disease.

作者信息

Shen Kangjun, Liu Hui, Jing Ran, Yi Jiangfeng, Zhou Xinmin

机构信息

Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, 139. Renmin Road, Changsha, Hunan, 410011, People's Republic of China.

Department of Hemodialysis Center, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.

出版信息

BMC Cardiovasc Disord. 2017 Jun 17;17(1):159. doi: 10.1186/s12872-017-0585-3.

DOI:10.1186/s12872-017-0585-3

PMID:28623907

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5474061/

Abstract

BACKGROUND

The epigenetic changes underlying the development of rheumatic heart valve disease (RHVD) remain incompletely understood. Limited evidence suggests that abnormal DNA methylation might be involved in the pathogenesis of RHVD. In the present study, we evaluated the DNA methylation dysregulations from myocardial tissue in RHVD patients systematically.

METHODS

Right atrial myocardial tissue obtained from rheumatic valvular patients who had undergone valve replacements surgery (n = 73) and were compared to healthy controls (n = 4). the promoter methylation level of Intercellular adhesion molecule-1 (ICAM-1) gene and its correlation with ICAM-1 mRNA expression level, the global DNA methylation level and its correlation with age and mRNA expression level of DNA methyltransferase (DNMT) genes were detected.

RESULTS

The ICAM-1 mRNA expression was increased (healthy control vs. NHYA III, 0.70 ± 0.19 vs. 4.38 ± 3.19, p = 0.011; NYHA IIvs. NHYA III, 2.60 ± 1.99 vs. 4.38 ± 3.19, p = 0.008) and the ICAM-1 gene was hypomethylated in RHVD patients (healthy controls vs. NYHA II, 0.120 ± 0.011 vs. 0.076 ± 0.057, p = 0.039; healthy control vs. NHYA III, 0.120 ± 0.011 vs. 0.041 ± 0.022, p < 0.001; NYHA IIvs. NHYA III, 0.076 ± 0.057 vs. 0.041 ± 0.022, p < 0.001). Meanwhile, The ICAM-1 mRNA expression level has negative correlation with the mean methylation level in the promoter region of ICAM-1 gene (r = -0.459, p < 0.001). The global DNA methylation levels was significantly increased in RHVD patients than in healthy controls (healthy control vs. NHYA III, 0.77 ± 0.28 vs. 2.09 ± 1.20, p = 0.017; NYHA IIvs. NHYA III, 1.57 ± 0.78 vs. 2.09 ± 1.20, p = 0.040) and had positive correlation with age (r = 0.326, p = 0.005), especially for older age group (≥ 60 years). DNMT1 likely plays an essential role in the DNA dysregulations in RHVD patients.

CONCLUSIONS

Our analysis revealed that DNA methylation dysregulations may be relevant in the pathogenesis of RHVD.

摘要

背景

风湿性心脏瓣膜病（RHVD）发生发展过程中的表观遗传变化仍未完全明确。有限的证据表明，异常的DNA甲基化可能参与了RHVD的发病机制。在本研究中，我们系统评估了RHVD患者心肌组织中的DNA甲基化失调情况。

方法

从接受瓣膜置换手术的风湿性瓣膜病患者（n = 73）获取右心房心肌组织，并与健康对照者（n = 4）进行比较。检测细胞间黏附分子-1（ICAM-1）基因的启动子甲基化水平及其与ICAM-1 mRNA表达水平的相关性、整体DNA甲基化水平及其与年龄和DNA甲基转移酶（DNMT）基因mRNA表达水平的相关性。

结果

RHVD患者中ICAM-1 mRNA表达增加（健康对照者与纽约心脏协会[NYHA] III级患者相比，0.70±0.19对4.38±3.19，p = 0.011；NYHA II级患者与NYHA III级患者相比，2.60±1.99对4.38±3.19，p = 0.008），且ICAM-1基因发生低甲基化（健康对照者与NYHA II级患者相比，0.120±0.011对0.076±0.057，p = 0.039；健康对照者与NYHA III级患者相比，0.120±0.011对0.041±0.022，p < 0.001；NYHA II级患者与NYHA III级患者相比，0.076±0.057对0.041±0.022，p < 0.001）。同时，ICAM-1 mRNA表达水平与ICAM-1基因启动子区域的平均甲基化水平呈负相关（r = -0.459，p < 0.001）。RHVD患者的整体DNA甲基化水平显著高于健康对照者（健康对照者与NYHA III级患者相比，0.77±0.28对2.09±1.20，p = 0.017；NYHA II级患者与NYHA III级患者相比，1.57±0.78对2.09±1.20，p = 0.040），且与年龄呈正相关（r = 0.326，p = 0.005），尤其是在老年组（≥60岁）。DNMT1可能在RHVD患者的DNA失调中起关键作用。