Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China.
Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, PR China.
J Mol Cell Cardiol. 2019 Mar;128:26-37. doi: 10.1016/j.yjmcc.2019.01.011. Epub 2019 Jan 17.
DNA methylation is a well-defined epigenetic modification that regulates gene transcription. However, the role of DNA methylation in the cardiac hypertrophy seen in hypertension is unclear. This study was performed to investigate genome-wide DNA methylation profiles in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKY), and the cardioprotective effect of choline. Eight-week-old male SHRs received intraperitoneal injections of choline (8 mg/kg/day) for 8 weeks. SHRs showed aberrant methylation distribution on chromosomes and genome regions, with decreased methylation levels at CHG and CHH sites. A total of 91,559 differentially methylated regions (DMRs) were detected between SHRs and WKY rats, of which 28,197 were demethylated and 63,362 were methylated. Choline treatment partly restored the DMRs in SHRs, which were related to 131 genes. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes analysis of DMRs suggested that choline partly reversed the dysfunctions of biological processes, cellular components and molecular functions in SHRs. Moreover, the inhibition of 2-oxoglutarate accumulation by choline, thereby inhibiting excessive activation of ten-eleven translocation methylcytosine dioxygenase enzymes, may correlate with the beneficial effects of choline on methylation levels, cardiac hypertrophy and cardiac function of SHRs, as indicated by decreased heart rate and blood pressure, and increased ejection fraction and fractional shortening. This study provides the first genome-wide DNA methylation profile of the hypertrophic myocardium of SHRs and suggests a novel role for this epigenetic modification in hypertension. Choline treatment may represent a promising approach for modification of DNA methylation and optimization of the epigenetic profile for antihypertensive therapy.
DNA 甲基化是一种明确的表观遗传修饰，可调节基因转录。然而，DNA 甲基化在高血压引起的心肌肥厚中的作用尚不清楚。本研究旨在探讨自发性高血压大鼠（SHR）和 Wistar-Kyoto 大鼠（WKY）的全基因组 DNA 甲基化谱，并研究胆碱的心脏保护作用。8 周龄雄性 SHR 接受腹腔内注射胆碱（8mg/kg/天）8 周。SHR 表现出染色体和基因组区域异常的甲基化分布，CHG 和 CHH 位点的甲基化水平降低。在 SHR 和 WKY 大鼠之间共检测到 91559 个差异甲基化区域（DMR），其中 28197 个去甲基化，63362 个甲基化。胆碱治疗部分恢复了 SHR 中的 DMR，这些 DMR 与 131 个基因有关。DMR 的基因本体分析和京都基因与基因组百科全书分析表明，胆碱部分逆转了 SHR 中生物过程、细胞成分和分子功能的功能障碍。此外，胆碱抑制 2-氧戊二酸的积累，从而抑制十-十一易位甲基胞嘧啶双加氧酶的过度激活，这可能与胆碱对 SHR 甲基化水平、心肌肥厚和心脏功能的有益作用相关，表现为心率和血压降低，射血分数和缩短分数增加。本研究提供了 SHR 肥厚心肌的全基因组 DNA 甲基化图谱，并提示这种表观遗传修饰在高血压中的新作用。胆碱治疗可能代表一种有前途的方法，用于修饰 DNA 甲基化并优化抗高血压治疗的表观遗传谱。
