Department of Laboratory Medicine, Peking Union Medical College Hospital and Peking Union Medical College, Beijing 100021, PR China.
State Key Laboratory of Molecular Oncology, Department of Clinical Laboratory, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China.
Aging (Albany NY). 2020 Apr 13;12(7):6276-6291. doi: 10.18632/aging.103023.
DNA methylation has a role in the pathogenesis of essential hypertension. DNA N6-methyladenine (6mA) modification as a novel adenine methylation exists in human tissues, but whether it plays a role in hypertension development remains unclear. Here, we reported that the global 6mA DNA level in leukocytes was significantly reduced in patients with hypertension and was reversed with successful treatment. Age, systolic blood pressure, and serum total cholesterol and high-density lipoprotein levels were associated with decreased leukocyte 6mA DNA level. Elevated ALKBH1 (AlkB homolog 1), a demethylase of 6mA, level mediated this dynamic change in 6mA level in leukocytes and vascular smooth muscle cells in hypertension mouse and rat models. Knockdown of ALKBH1 suppressed angiotensin II-induced vascular smooth muscle phenotype transformation, proliferation and migration. ALKBH1-6mA directly and negatively regulated hypoxia inducible factor 1 α (HIF1α), which responded to angiotensin II-induced vascular remodeling. Collectively, our results demonstrate a potential epigenetic role for ALKBH1-6mA regulation in hypertension development, diagnosis and treatment.
DNA 甲基化在原发性高血压的发病机制中起作用。DNA N6-甲基腺嘌呤（6mA）修饰作为一种新型腺嘌呤甲基化存在于人体组织中，但它在高血压发展中的作用尚不清楚。在这里，我们报道白细胞中的全基因组 6mA DNA 水平在高血压患者中显著降低，并随着成功治疗而逆转。年龄、收缩压以及血清总胆固醇和高密度脂蛋白水平与白细胞 6mA DNA 水平降低有关。在高血压小鼠和大鼠模型中，ALKBH1（AlkB 同源物 1）水平升高，ALKBH1 是 6mA 的一种去甲基化酶，介导了白细胞和血管平滑肌细胞中 6mA 水平的这种动态变化。ALKBH1 敲低抑制血管紧张素 II 诱导的血管平滑肌表型转化、增殖和迁移。ALKBH1-6mA 直接负调控缺氧诱导因子 1α（HIF1α），而 HIF1α 对血管紧张素 II 诱导的血管重塑有反应。综上所述，我们的研究结果表明，ALKBH1-6mA 调节在高血压的发生、诊断和治疗中具有潜在的表观遗传作用。
