Involvement of histone methylation in macrophage apoptosis and unstable plaque formation in methionine-induced hyperhomocysteinemic ApoE-/- mice
Involvement of histone methylation in macrophage apoptosis and unstable plaque formation in methionine-induced hyperhomocysteinemic ApoE-/- mice
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DOI：
10.1016/j.lfs.2017.02.003
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发表时间：
2017-03-15
期刊：
影响因子：
6.1
通讯作者：
Jia, Shaobin
中科院分区：
文献类型：
--
作者：
Cong, Guangzhi;Yan, Ru;Jia, Shaobin
目的：高同型半胱氨酸血症(Hhcy)是动脉粥样硬化的独立危险因素，促进不稳定斑块的形成。表观遗传机制在同型半胱氨酸诱导的动脉粥样硬化发病机制中起重要作用。然而，确切的机制仍未确定。病变的凋亡细胞和坏死核的形成对斑块的进展有很大的作用。本研究旨在探讨组蛋白甲基化修饰是否参与Hhcy状态下巨噬细胞的凋亡和不稳定斑块的形成。材料和方法：观察高蛋氨酸(HM)饮食诱导的Hhcy ApoE(-/-)小鼠主动脉不稳定斑块形成、病变细胞凋亡和组蛋白甲基化状态。用同型半胱氨酸单独或与组蛋白甲基化抑制剂Bix01294联合作用于巨噬细胞Raw 264.7细胞，研究了组蛋白甲基化在巨噬细胞凋亡和泡沫细胞形成中的作用。关键发现：ApoE(-/-)小鼠补充高蛋氨酸(HM)后，不稳定的斑块形成和损伤的凋亡细胞增加，伴随着组蛋白H3赖氨酸9二甲基化表达的减少。Hhcy在体外可促进巨噬细胞的凋亡，抑制组蛋白H3赖氨酸9的二甲基化，并抑制组蛋白甲基转移酶G9a的表达。BIX01294抑制组蛋白甲基化促进巨噬细胞的凋亡和泡沫细胞的形成。意义：我们的数据提示Hhcy通过巨噬细胞的凋亡促进动脉粥样硬化的进展。组蛋白甲基化可能参与蛋氨酸诱导的高同型半胱氨酸血症ApoE(-/-)小鼠巨噬细胞的凋亡和不稳定斑块的形成。(C)2017 Elsevier Inc.保留所有权利。
Aims: Hyperhomocysteinemia (Hhcy) is an independent risk factor of atherosclerosis and promotes unstable plaque formation. Epigenetic mechanisms play an important role in the pathogenesis of atherosclerosis induced by Hhcy. However, the exact mechanism is still undefined. Lesional apoptotic cells and necrotic core formation contribute greatly to the progression of plaque. The present study sought to determine whether modification of histone methylation is involved in macrophage apoptosis and unstable plaque formation in the condition of Hhcy.Materials and methods: The unstable plaque formation, lesional apoptotic cells and status of histone methylation were monitored in the aortas of Hhcy ApoE(-/-) mice induced by a high-methionine (HM) diet for 20 weeks. Involvement of histone methylation in macrophage apoptosis and foam cell formation were assessed in macrophage Raw 264.7 cells after being challenged with homocysteine alone or in combination with the histone methylation inhibitor BIX 01294.Key findings: The unstable plaque formation and lesion apoptotic cells are increased in ApoE(-/-) mice supplemented with high-methionine (HM), accompanied with a decreased expression of histone H3 lysine 9 dimethylation. Hhcy increases the apoptosis of macrophages and inhibits the histone H3 lysine 9 dimethylation, as well as the expression of histone methyltransferase G9a in vitro. Inhibition of histone methylation by BIX01294 enhances macrophage apoptosis and foam cell formation in vitro.Significance: Our data suggest that Hhcy promotes the progression of atherosclerosis via macrophage apoptosis. Histone methylation might be involved in macrophage apoptosis and unstable plaque formation in methionine induced hyperhomocysteinemic ApoE(-/-) mice. (C) 2017 Elsevier Inc. All rights reserved.