Medical college, Hangzhou Normal University, No.16 Xuelin Road, Xiasha Higher Education Park, Hangzhou, China.
Medical college, Hangzhou Normal University, No.16 Xuelin Road, Xiasha Higher Education Park, Hangzhou, China.
Toxicology. 2019 Aug 1;424:152225. doi: 10.1016/j.tox.2019.05.012. Epub 2019 May 28.
Growing evidences indicate that epigenetic modification involves in the mechanisms of atherosclerosis, which intersects with oxidative stress pathway. Arsenic is an important environmental contaminant and has been linked to atherosclerosis. However, the exact mechanism is not well understood. In the present study, we analyzed the effect of arsenic on oxidative stress, ABCA1 promoter methylation and cholesterol efflux of THP-1 macrophages. Results showed that arsenic could induce ROS-mediated DNA methyltransferase 1 (DNMT1) transcription and activity up-regulation, causing ABCA1 promoter to be hypermethylated with repressed expression. In addition, arsenic depleted the methyl donor S-adenosylmethionine (SAM) and induced global DNA hypomethylation. Arsenic inhibited cholesterol efflux of THP-1 macrophages, which could be attenuated after pretreatment with NAC or DNMT inhibitor 5-Aza-2'-deoxycytidine, but not with SAM. All of the findings suggest that arsenic inhibit cholesterol efflux of THP-1 macrophages via ROS-mediated ABCA1 hypermethylation.
越来越多的证据表明，表观遗传修饰参与了动脉粥样硬化的发生机制，这与氧化应激途径相互交叉。砷是一种重要的环境污染物，与动脉粥样硬化有关。然而，其确切机制尚不清楚。在本研究中，我们分析了砷对 THP-1 巨噬细胞氧化应激、ABCA1 启动子甲基化和胆固醇流出的影响。结果表明，砷可诱导 ROS 介导的 DNA 甲基转移酶 1（DNMT1）转录和活性上调，导致 ABCA1 启动子超甲基化，表达受抑制。此外，砷耗竭甲基供体 S-腺苷甲硫氨酸（SAM）并诱导全基因组 DNA 低甲基化。砷抑制 THP-1 巨噬细胞的胆固醇流出，这一作用可被 NAC 或 DNA 甲基转移酶抑制剂 5-Aza-2'-脱氧胞苷预处理所减弱，但 SAM 预处理无效。所有这些发现表明，砷通过 ROS 介导的 ABCA1 高甲基化抑制 THP-1 巨噬细胞的胆固醇流出。
