Abstract
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.
Highlights
Essential hypertension is the number 1 identifiable risk factor for death worldwide [1] and it affects both sexes, mainly older patients [2, 3]
6mA DNA level was negatively correlated with systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) in hypertension patients (Figure 1B)
Given that AlkB homolog 1 (ALKBH1) mediated 6mA DNA modificationsignature hypoxia-response genes [21], we focused on hypoxia inducible factor 1 α (HIF1α), which is required for Ang Angiotensin II (II)-induced vascular remodeling [23]
Summary
Essential hypertension is the number 1 identifiable risk factor for death worldwide [1] and it affects both sexes, mainly older patients [2, 3]. This age-related condition affects about a quarter of the adult population, with severe complications. Genetic and epigenetic components have a prominent role in the development of essential hypertension [4]. As compared with genetic factors, changed epigenetics are reversible with the progression and treatment of hypertension [5, 6]. Epigenetic measurement and therapy confers new ideas and methods for the diagnosis and treatment of hypertension
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