Toxicology 2014-09-02

DNMT3A silencing RASSF1A promotes cardiac fibrosis through upregulation of ERK1/2.

Hui Tao, Jing-Jing Yang, Ze-Wen Chen, Sheng-Song Xu, Xiao Zhou, Hong-Ying Zhan, Kai-Hu Shi

Index: Toxicology 323 , 42-50, (2014)

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Abstract

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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.