DNA methylation in cystathionine-γ-lyase (CSE) gene promoter induced by ox-LDL in macrophages and in apoE knockout mice
DNA methylation in cystathionine-γ-lyase (CSE) gene promoter induced by ox-LDL in macrophages and in apoE knockout mice
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DOI：
10.1016/j.bbrc.2015.11.132
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发表时间：
2016-01-15
影响因子：
3.1
通讯作者：
Liu, Chun-Feng
中科院分区：
文献类型：
--
作者：
Du, Hua-Ping;Li, Jiaojiao;Liu, Chun-Feng
最近的研究表明，DNA甲基化等表观遗传改变控制着单核/巨噬细胞的许多方面，并参与了动脉粥样硬化的发病机制，动脉粥样硬化是一种脂质驱动的炎症性疾病。OUR和其他研究小组证实，CSE-硫化氢途径的失调参与了单核/巨噬细胞介导的炎症和动脉粥样硬化。然而，目前尚不清楚巨噬细胞中CSE甲基化改变是否在CSE-H_2S调节失调和动脉粥样硬化之间起作用。在本研究中，我们发现载脂蛋白基因敲除(apoE(-/-))小鼠的血浆H_2S和巨噬细胞中H_2S的产生随着年龄的增长而逐渐减少，在12周龄时也低于正常小鼠。此外，与年龄匹配的野生型小鼠相比，apoE(-/-)小鼠的腹膜巨噬细胞CSE mRNA表达减少，而DNA甲基转移酶(DNMT)表达增加。在体外研究中也得到了类似的观察结果。在氧化低密度脂蛋白(ox-LDL)处理的RAW 264.7巨噬细胞中，CSE转录下调，而DNMT的表达和活性上调，这与CSE启动子DNA甲基化增强有关。用其抑制剂或siRNA抑制DNMT可逆转CSE基因表达的下降。因此，我们的研究结果提示，CSE启动子中CpG富集区的DNA高甲基化可能导致巨噬细胞CSE转录和H_2S生成减少，从而导致动脉粥样硬化的发生。(C)2015 Elsevier Inc.保留所有权利。
Recent studies suggest that epigenetic alterations such as DNA methylation control many aspects of monocytes/macrophages and participate in the pathogenesis of atherosclerosis, a lipid-driven inflammatory disorder. Our and other groups demonstrated that dysregulation of cystathionine gamma-lyase (CSE)-hydrogen sulfide (H2S) pathway was involved in monocyte/macrophages-mediated inflammation and atherosclerosis. However, it remains unknown whether altered cse methylation in macrophages may play a role in linking CSE-H2S dysregulation and atherosclerosis. In the present study, we showed that plasma H2S and H2S production in the peritoneal macrophages of apolipoprotein knockout (apoE(-/-)) mice gradually decreased with ages, and were also lower than that in control mice at 12 weeks older. Moreover, CSE mRNA expressions decreased while DNA methyltransferase (DNMT) expressions increased in the peritoneal macrophages isolated from apoE(-/-) mice, compared to age-matched wildtype mice. Similar observations were obtained in an in vitro study. In oxidized low-density lipoprotein (ox-LDL)-treated raw264.7 macrophages, cse transcription was down-regulated while the expression and activity of DNMT was up-regulated, associated with enhanced DNA methylation in cse promoter. Suppression of DNMT with its inhibitor or siRNA reversed the decrease of CSE mRNA. Therefore, our data suggest that DNA hypermethylation of CpG rich region in cse promoter might contribute to the decrease of cse transcription and H2S production in macrophages, and thus contribute to atherosclerosis development. (C) 2015 Elsevier Inc. All rights reserved.