Department of Cardiovascular Medicine Fukushima Medical University Fukushima Japan.
Department of Arrhythmia and Cardiac Pacing Fukushima Medical University Fukushima Japan.
J Am Heart Assoc. 2021 Nov 2;10(21):e021101. doi: 10.1161/JAHA.121.021101. Epub 2021 Oct 29.
Background Blood-based DNA methylation patterns are linked to types of diseases. FKBP prolyl isomerase 5 (FKBP5), a protein cochaperone, is known to be associated with the inflammatory response, but the regulatory mechanisms by leukocyte DNA methylation in patients with dilated cardiomyopathy (DCM) remain unclear. Methods and Results The present study enrolled patients with DCM (n=31) and age-matched and sex-matched control participants (n=43). We assessed CpG (cytosine-phosphate-guanine) methylation of CpG islands at the 5' side as well as putative promoter regions by methylation-specific quantitative polymerase chain reaction using leukocyte DNA isolated from the peripheral blood. CpG methylation levels at the CpG island of the gene body and the promoter regions were significantly decreased in patients with DCM. Leukocyte and (interleukin 1β) mRNA expression levels were significantly higher in patients with DCM than in controls. The protein expressions of DNMT1 (DNA methyltransferase 1) and DNMT3A (DNA methyltransferase 3A) in leukocytes were significantly reduced in patients with DCM. In vitro methylation assay revealed that promoter activity was inhibited at the methylated conditions in response to immune stimulation, suggesting that the decreased CpG methylation was functionally associated with elevation of mRNA expressions. Histological analysis using a mouse model with pressure overload showed that FKBP5-expressing cells were substantially infiltrated in the myocardial interstitium in the failing hearts, indicating a possible role of FKBP5 expressions of immune cells in the cardiac remodeling. Conclusions Our findings demonstrate a link between specific CpG hypomethylation of leukocyte and DCM. Blood-based epigenetic modification in may be a novel molecular mechanism that contributes to the pathogenesis of DCM.
背景 基于血液的 DNA 甲基化模式与疾病类型有关。FKBP 脯氨酰异构酶 5（FKBP5）是一种蛋白质共伴侣，已知与炎症反应有关，但白细胞 DNA 甲基化在扩张型心肌病（DCM）患者中的调控机制尚不清楚。 方法和结果 本研究纳入了 31 例 DCM 患者和年龄、性别匹配的对照组参与者（n=43）。我们使用从外周血中分离的白细胞，通过甲基化特异性定量聚合酶链反应评估了基因体和启动子区域的 CpG（胞嘧啶-磷酸-鸟嘌呤）岛的 CpG 甲基化。DCM 患者的基因体和启动子区域的 CpG 岛甲基化水平显著降低。DCM 患者的白细胞和（白细胞介素 1β）mRNA 表达水平明显高于对照组。DCM 患者白细胞中的 DNMT1（DNA 甲基转移酶 1）和 DNMT3A（DNA 甲基转移酶 3A）蛋白表达明显降低。体外甲基化试验显示，在免疫刺激下，启动子活性在甲基化条件下受到抑制，这表明 CpG 甲基化的降低与 mRNA 表达的升高具有功能相关性。使用压力超负荷的小鼠模型进行的组织学分析表明，FKBP5 表达细胞在衰竭心脏的心肌间质中大量浸润，表明免疫细胞中 FKBP5 表达可能在心脏重构中发挥作用。 结论 我们的研究结果表明，白细胞中特定的 CpG 低甲基化与 DCM 之间存在关联。白细胞中基于血液的表观遗传修饰可能是导致 DCM 发病机制的新分子机制。
