Homocysteine-induced oxidative stress through TLR4/NF-κB/DNMT1-mediated LOX-1 DNA methylation in endothelial cells
Homocysteine-induced oxidative stress through TLR4/NF-κB/DNMT1-mediated LOX-1 DNA methylation in endothelial cells
复制标题
同型半胱氨酸通过 TLR4/NF-kappa B/DNMT1 介导的内皮细胞 LOX-1 DNA 甲基化诱导氧化应激
DOI：
10.3892/mmr.2017.7753
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发表时间：
2017-12-01
影响因子：
3.4
通讯作者：
Zhang, Hui-Ping
中科院分区：
文献类型：
--
作者：
Ma, Sheng-Chao;Hao, Yin-Ju;Zhang, Hui-Ping
动脉粥样硬化（AS）是一种多因素起源的进行性疾病，其发生是对内皮损伤的反应。同型半胱氨酸（Hcy）水平升高被认为是导致内皮功能障碍、氧化应激和DNA甲基化的主要原因，但其机制尚不清楚。本研究的目的是探讨同型半胱氨酸是否通过Toll样受体4（TLR 4）/核因子（NF）-κ B/DNA甲基转移酶（DNMT）1影响凝集素样氧化低密度脂蛋白受体1（LOX-1）DNA甲基化而导致内皮细胞损伤。用不同浓度的同型半胱氨酸处理内皮细胞，发现同型半胱氨酸促进TLR 4的表达，导致内皮细胞损伤。通过测定内皮细胞中的超氧化物歧化酶、丙二醛和过氧化氢来分析氧化应激的影响。此外，NF-κ B B和DNMT 1之间的关联通过用吡咯烷二硫代氨基甲酸酯（PDTC）处理EC来检查。结果提示，Hcy可诱导LOX-1 DNA甲基化降低，从而促进LOX-1的表达。Hcy通过TLR 4/NF-κ B B/DNMT 1介导LOX-1的甲基化和转硫代谢，损伤内皮细胞。内皮细胞损伤后，脂质，特别是ox-LDL，在内皮下层积累，促进AS的形成。
Atherosclerosis (AS) is a progressive disease of multifactorial origin, which occurs in response to endothelial injury. Increased homocysteine (Hcy) is considered a major cause of endothelial dysfunction, oxidative stress and DNA methylation; however, the mechanisms remain to be fully elucidated. The aim of the present study was to investigate whether Hcy causes injury to endothelial cells (ECs) by the effect of lectin-like oxidized-low density lipoprotein receptor-1 (LOX-1) DNA methylation through toll-like receptor 4(TLR4)/nuclear factor (NF)-kappa B/DNA methyltransferase (DNMT)1. The ECs were treated with different concentrations of Hcy, and it was found that Hcy promoted the expression of TLR4, leading to EC injury. The effect of oxidative stress was analyzed by measuring superoxide dismutase, malondialdehyde and hydrogen peroxide in the ECs. In addition, the association between NF-kappa B and DNMT1 was examined by treatment of the ECs with pyrrolidine dithiocarbamate (PDTC). The results suggested that Hcy induced LOX-1 DNA hypomethyaltion to promote the expression levels of LOX-1. Taken together, Hcy injured the ECs through the effect of methylation and trans-sulfuration metabolism of LOX-1 through TLR4/NF-kappa B/DNMT1. Following injury to the ECs, lipids, particularly ox-LDL, accumulated in the sub-endothelial layer to promote the formation of AS.