DNMT3A silencing RASSF1A promotes cardiac fibrosis through upregulation of ERK1/2
DNMT3A silencing RASSF1A promotes cardiac fibrosis through upregulation of ERK1/2
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DOI：
10.1016/j.tox.2014.06.006
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发表时间：
2014-09-02
期刊：
影响因子：
4.5
通讯作者：
Shi, Kai-Hu
中科院分区：
文献类型：
--
作者：
Tao, Hui;Yang, Jing-Jing;Shi, Kai-Hu
心脏纤维化是心房颤动（AF）的发病机制之一。心肌纤维化的分子机制尚不清楚。然而，Ras相关结构域家族1亚型A（RASSF 1A）是调节性肿瘤抑制因子，其在心脏纤维化和成纤维细胞活化的发病机制中是重要的。此外，DNA甲基化在心脏纤维化的维持中起着核心作用。DNA甲基转移酶3A（DNMT 3A）是调控基因表观遗传沉默的重要参与者。在这里，我们报告RASSF 1A在心脏纤维化中的下调与DNMT 3A相关。用DNMT 3A抑制剂5-AzadC处理心脏成纤维细胞阻断增殖。5-AzadC还防止了在激活心脏成纤维细胞期间发生的RASSF 1A表达的丧失。为了确定潜在的分子机制，我们假设心脏纤维化是由DNMT 3A控制的。我们证明RASSF 1A的下调与心脏纤维化和成纤维细胞活化有关。DNMT 3A的敲低提高了活化的心脏成纤维细胞中RASSF 1A的表达。此外，我们研究了RASSF 1A对Ras/ERK通路的影响。在RASSF 1A表达降低的激活的心脏成纤维细胞中检测到p-ERK 1/2的上调。我们的研究结果表明，DNMT 3A可能在大鼠心脏纤维化中RASSF 1A介导的ERK 1/2上调中起重要作用。DNMT 3A和RASSF 1A可能是心肌纤维化的新机制。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Cardiac fibrosis contributes to the pathogenesis of atrial fibrillation (AF). The molecular mechanisms underlying the cardiac fibrosis remain unclear. However, Ras association domain family 1 isoform A (RASSF1A) is a regulatory tumor suppressor, which is important for pathogenesis of cardiac fibrosis and fibroblasts activation. Moreover, DNA methylation plays a central role in the maintenance of cardiac fibrosis. DNA methyltransferases 3A (DNMT3A) is a critical participant in the epigenetic silencing of regulatory genes. Here, we report that the downregulation of RASSF1A in cardiac fibrosis is associated with DNMT3A. Treatment of cardiac fibroblasts with DNMT3A inhibitor 5-AzadC blocked proliferation. 5-AzadC also prevented the loss of RASSF1A expression that occurs during activated cardiac fibroblasts. To determine the underlying molecular mechanisms, we hypothesized that cardiac fibrosis is controlled by DNMT3A. We demonstrated that downregulation of RASSF1A is associated with cardiac fibrosis and fibroblasts activation. Knockdown of DNMT3A elevated RASSF1A expression in activated cardiac fibroblasts. Moreover, we investigated the effect of RASSF1A on the Ras/ERK pathway. Upregulation of p-ERK1/2 was detected in activated cardiac fibroblasts with decreased RASSF1A expression. Our results have shown that DNMT3A likely plays an essential role in RASSF1A mediated upregulation of ERK1/2 in rat cardiac fibrosis. DNMT3A and RASSF1A may serve as a new mechanism for cardiac fibrosis. (C) 2014 Elsevier Ireland Ltd. All rights reserved.