DNA N6-methyladenine modification in hypertension

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.

ALKBH1-demethylated DNA N6-methyladenine modification triggers vascular calcification via osteogenic reprogramming in chronic kidney disease

“…The blood pressure of CKD patients showed difference between Non-VC and VC group (Table 1). In addition, ALKBH1 was associated with hypertension (19). However, we found systolic blood pressure, diastolic blood pressure, and other parameters including blood glucose, cholesterol, and triglyceride were not affected by ALKBH1 deficiency or overexpression in vivo (Supplemental Table 1-3, Supplemental Figure 7).…”

“…Several studies revealed that there is a robust relationship between ALKBH1demethylated DNA 6mA modification and cardiovascular diseases, such as hypertension and atherosclerosis (18,19). As previously reported, ALKBH1-mediated 6mA demethylation is required for the osteogenic differentiation of human mesenchymal stem cells during bone metabolism (20).…”

“…A set of VSMCs contractile and osteogenic genes, including klotho (12), TAGLN (15), and peroxisome proliferator-activated receptor gamma (33) are regulated by DNA 5mC methylation that could be consequently associated with VSMCs phenotypic transition and pathogenesis of VC. In addition to the genome-wide DNA 5mC, recently ALKBH1-mediated 6mA DNA demethylation was identified in human cardiovascular diseases (19). However, it remains unknown whether VSMCs can adopt novel epigenetic mechanisms that are rarely utilized in normal human tissues during VC.…”

YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation

“…The enrichment of certain fragments was determined using real-time PCR. The enrichment of the RNAs was normalized to inputs from the siRNA control group [ 31 , 32 ].…”

Roles and Mechanisms of DNA Methylation in Vascular Aging and Related Diseases

“…The senescence of vascular cells promotes arterial stiffness, causing hypertension (Qiu et al, 2010;Chi et al, 2019). DNA methylation is involved in hypertension (Gao et al, 2018;Guo et al, 2020;Amenyah et al, 2021). Kazmi et al investigated the relationship between hypertension and DNA methylation in European men and discovered that 7 CpG sites were related to diastolic blood pressure (Kazmi et al, 2020).…”