SNF5 promotes IL-1β expression via H3K4me1 in atherosclerosis induced by homocysteine.
SNF5 promotes IL-1β expression via H3K4me1 in atherosclerosis induced by homocysteine.
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SNF5 通过 H3K4me1 在同型半胱氨酸诱导的动脉粥样硬化中促进 IL-1β 表达
DOI：
10.1016/j.biocel.2021.105974
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Jiang Yideng
中科院分区：
文献类型：
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作者：
Xie Lin;Ding Ning;Zhang Honghong;Liu Kun;Xiong Jiantuan;Ma Shengchao;Yang Anning;Zhang Huiping;Jiang Yideng
同型半胱氨酸（Homocysteine，Hcy）是动脉粥样硬化的独立危险因子。它可通过增加炎症因子尤其是白细胞介素-1 β（IL-1β）的产生而加速动脉粥样硬化，但其确切机制尚不清楚。本研究旨在探讨开关/蔗糖非发酵复合物（SWI/SNF）相关的肿瘤抑制基因SNF 5在同型半胱氨酸诱导的动脉粥样硬化发生发展中的作用。使用高同型半胱氨酸血症（HHcy）动脉粥样硬化模型与载脂蛋白E敲除（ApoE−/−）小鼠喂养高蛋氨酸饮食，我们表明，同型半胱氨酸加剧炎症巨噬细胞在动脉粥样硬化斑块形成。进一步分析表明，SNF 5促进IL-1β的表达和分泌。此外，由于IL-1β附近存在H3 K4甲基化信号，我们发现Hcy显著促进H3 K4 me 1的表达，赖氨酸特异性组蛋白去甲基化酶1A（KDM 1A）作为转录抑制因子通过去甲基化H3 K4 me 1来调控H3 K4 me 1的表达。综上所述，我们的研究结果表明，Hcy通过KDM 1A上调SNF 5的表达，导致巨噬细胞中H3 K4 me 1修饰和IL-1β水平升高，进而促进动脉粥样硬化的形成。我们的研究将为进一步揭示同型半胱氨酸诱导炎症的具体机制以及动脉粥样硬化的诊断、预防和治疗提供更多证据。
Homocysteine (Hcy) is a strong and independent risk factor of atherosclerosis. It can accelerate atherosclerosis through increased production of inflammatory factors, especially interleukin-1 β (IL-1β), while the precise mechanisms remain to be well elucidated. In this study, we investigated the role of the tumor suppressor gene SNF5 related to switch/sucrose non-fermentable complex (SWI/SNF) in the occurrence and development of atherosclerosis induced by Hcy. Using Hyperhomocysteinemia (HHcy) atherosclerotic model with apolipoprotein E knockout (ApoE−/−) mice fed with high-methionine diet, we showed that Hcy aggravates inflammation in macrophages during the atherosclerotic plaque formation. Further analysis showed that SNF5 promotes IL-1β expression and secretion. In addition, due to the existence of H3K4 methylation signals in the vicinity of IL-1β, we found that Hcy significantly promotes the expression of H3K4me1, and lysine-specific histone demethylase 1A (KDM1A) acts as a transcriptional repressor to regulate the expression of H3K4me1 by demethylating H3K4me1. In summary, our results demonstrated that Hcy up-regulates the expression of SNF5 through KDM1A, resulting in an increased level of H3K4me1 modification and IL-1β in macrophages, which in turn promotes the formation of atherosclerosis. Our study will provide more evidence for further revealing the specific mechanism of Hcy-induced inflammation and the diagnosis, prevention, and treatment of atherosclerosis.