Introduction:

Recent evidence suggests that transcriptional reprogramming is involved in the pathogenesis of cardiac remodeling (cardiomyocyte hypertrophy and fibrosis) and the development of heart failure. 5-Azacytidine (5aza), an inhibitor of DNA methylation approved for hematological malignancies, has previously demonstrated beneficial effects on cardiac remodeling in hypertension. The aim of our work was to investigate whether pressure overload is associated with alterations in DNA methylation and if intervention with low-dose 5aza can attenuate the associated pathological changes.

Methods and Results:

C57Bl6/J mice underwent surgical constriction of the aortic arch for 8 weeks. Mice began treatment 4 weeks post-surgery with either vehicle or 5aza (5 mg/kg). Cardiac structure and function was examined in vivo using echocardiography followed by post mortem histological assessment of hypertrophy and fibrosis. Global DNA methylation was examined by immunostaining for 5-methylcytosine (5MeC) and assessment of DNA methyltransferase expression. The results highlighted that pressure overload-induced pathological cardiac remodeling is associated with increased DNA methylation (elevated cardiac 5MeC positivity and Dnmt1 expression). Administration of 5aza attenuated pathological remodeling and diastolic dysfunction. These beneficial changes were mirrored by a treatment-related reduction in global 5MeC levels and expression of Dnmt1 and Dnmt3B in the heart.

Conclusion:

DNA methylation plays an important role in the pathogenesis of pressure overload-induced cardiac remodeling. Therapeutic intervention with 5aza, at a dose 5 times lower than clinically given for oncology treatment, attenuated myocardial hypertrophy and fibrosis. Our work supports the rationale for its potential use in cardiac pathologies associated with aberrant cardiac wound healing.

中文翻译：

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从肿瘤学到心脏病学的再利用：低剂量 5-氮杂胞苷可减轻对压力过载损伤的病理性心脏重塑

介绍：

最近的证据表明，转录重编程与心脏重塑（心肌细胞肥大和纤维化）的发病机制和心力衰竭的发展有关。5-氮杂胞苷 (5aza) 是一种批准用于血液系统恶性肿瘤的 DNA 甲基化抑制剂，此前已证明对高血压患者的心脏重塑有益。我们工作的目的是调查压力超负荷是否与 DNA 甲基化的改变有关，以及低剂量 5aza 的干预是否可以减轻相关的病理变化。

方法和结果：

C57Bl6/J 小鼠接受了 8 周的主动脉弓手术收缩。小鼠在手术后 4 周开始用载体或 5aza (5 mg/kg) 进行治疗。在体内检查心脏结构和功能使用超声心动图，然后对肥大和纤维化进行死后组织学评估。通过免疫染色 5-甲基胞嘧啶 (5MeC) 和评估 DNA 甲基转移酶表达来检查整体 DNA 甲基化。结果强调，压力超负荷诱导的病理性心脏重塑与 DNA 甲基化增加（心脏 5MeC 阳性和 Dnmt1 表达升高）有关。施用 5aza 可减轻病理重塑和舒张功能障碍。这些有益的变化反映在与治疗相关的全球 5MeC 水平降低以及心脏中 Dnmt1 和 Dnmt3B 的表达上。

结论：

DNA甲基化在压力超负荷诱导的心脏重构的发病机制中起重要作用。5aza 的治疗性干预（剂量比临床肿瘤治疗剂量低 5 倍）减轻了心肌肥大和纤维化。我们的工作支持其在与异常心脏伤口愈合相关的心脏病理学中的潜在用途的基本原理。