Association of N(6)-methyladenine DNA with plaque progression in atherosclerosis via myocardial infarction-associated transcripts

Modification of the novel N(6)-methyladenine (m6A) DNA implicates this epigenetic mark in human malignant disease, but its role in atherosclerosis (AS) is largely unknown. Here, we found that the leukocyte level of m6A but not 5mC DNA modification was decreased with increasing of carotid plaque size and thickness in 207 AS patients as compared with 142 sex- and age-matched controls. Serum low-density lipoprotein (LDL) and leukocyte m6A levels were associated with the progression of carotid plaque size and thickness. Both LDL level and plaque thickness were also independently and negatively related to m6A level. Reduced m6A level was further confirmed in leukocytes and endothelium in western diet-induced AS mice and in oxidized-LDL (ox-LDL)-treated human endothelium and monocyte cells. Decreased m6A level was closely related to the upregulation of AlkB homolog 1 (ALKBH1), the demethylase of m6A. Silencing of ALKBH1 or hypoxia-inducible factor 1α (HIF1α) could rescue the ox-LDL–increased level of MIAT, a hypoxia-response gene. Mechanically, ox-LDL induced HIF1α for transfer into the nucleus. Nuclear HIF1α bound to the ALKBH1-demethylated MIAT promoter and transcriptionally upregulated its expression. Therefore, elevated ALKBH1 level in endothelium and leukocytes reduced m6A level, which is a novel and sensitive biomarker for AS progression.