EZH2 as a novel therapeutic target for atrial fibrosis and atrial fibrillation
EZH2 as a novel therapeutic target for atrial fibrosis and atrial fibrillation
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EZH2作为心房纤维化和心房颤动的新治疗靶点
DOI：
10.1016/j.yjmcc.2019.08.003
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发表时间：
2019-10-01
影响因子：
5
通讯作者：
Wang, Qunshan
中科院分区：
文献类型：
--
作者：
Song, Shuai;Zhang, Rui;Wang, Qunshan
血管紧张素II(Ang-II)诱导成纤维细胞分化在心房纤维化和房颤的发生发展中起重要作用。在此，我们发现组蛋白甲基转移酶增强子2(EZH2)在房颤患者的心房肌和心房成纤维细胞中的表达增加，并伴有明显的心房纤维化和心房成纤维细胞分化。此外，还在小鼠心房纤维化模型中诱导了EZH2。此外，药物GSK126抑制或分子沉默EZH2均可抑制Ang-II诱导的心房成纤维细胞分化和产生ECM的能力。同时，抑制EZH2可阻断Ang-II诱导的心房成纤维细胞迁移。我们发现，EZH2主要通过Smad信号通路促进成纤维细胞的分化，并能与Smad2形成转录复合体，与ACTA2基因的启动子区域结合。最后，我们的体内实验表明，EZH2抑制剂GSK126显著抑制Ang-II诱导的心房扩大和纤维化，并降低房颤的易感性。我们的结果表明，靶向EZH2或EZH2调节的基因可能在房颤中具有治疗潜力。
Angiotensin II (Ang-II)-induced fibroblast differentiation plays an important role in the development of atrial fibrosis and atrial fibrillation (AF). Here, we show that the expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is increased in atrial muscle and atrial fibroblasts in patients with AF, accompanied by significant atrial fibrosis and atrial fibroblast differentiation. In addition, EZH2 is induced in murine models of atrial fibrosis. Furthermore, either pharmacological GSK126 inhibition or molecular silencing of EZH2 can inhibit the differentiation of atrial fibroblasts and the ability to produce ECM induced by Ang-II. Simultaneously, inhibition of EZH2 can block the Ang-II-induced migration of atrial fibroblasts. We found that EZH2 promotes fibroblast differentiation mainly through the Smad signaling pathway and can form a transcription complex with Smad2 to bind to the promoter region of the ACTA2 gene. Finally, our in vivo experiments demonstrated that the EZH2 inhibitor GSK126 significantly inhibited Ang-II-induced atrial enlargement and fibrosis and reduced AF vulnerability. Our results demonstrate that targeting EZH2 or EZH2-regulated genes might present therapeutic potential in AF.