ABSTRACT
Modification of the novel N6-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.
Subject(s)
Adenine/analogs & derivatives , DNA/metabolism , Disease Progression , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/pathology , RNA, Long Noncoding/metabolism , Adenine/metabolism , AlkB Homolog 1, Histone H2a Dioxygenase/blood , Animals , DNA Methylation/drug effects , DNA Methylation/genetics , Demethylation/drug effects , Diet, Western , Disease Models, Animal , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Female , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Leukocytes/drug effects , Leukocytes/metabolism , Linear Models , Lipoproteins, LDL/blood , Lipoproteins, LDL/pharmacology , Male , Mice , Middle Aged , Multivariate Analysis , Plaque, Atherosclerotic/blood , Promoter Regions, Genetic/genetics , Protein Binding/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , THP-1 CellsABSTRACT
OBJECTIVE: To detect common environmental pollutants in human body. METHODS: Urine samples were collected from 80 healthy subjects. Chromatography mass spectrometry (GC-MS), HPLC and ELISA were applied to detect several common environmental pollutants in urine samples. RESULTS: DBP and methylbenzene were present in 75.3% and 41.2% of urine samples. The methanal and AFM1 were found in most of urine samples (approximately 91â97%). By contrast, PCBs, CPZ, 4, 5-DCC were found in less than 5 samples, but there was no TMT detected. CONCLUSION: Some of the environmental pollutants including carcinogens are detected in urine samples in this study.
