Increasing evidence has shown that microRNAs (miRNAs) participate in cardiac fibrosis. We aimed to elucidate the effect of miRNA miR-25-3p on cardiac fibrosis. MiRNA microarray was used to profile miRNAs in the myocardium of angiotensin-II (Ang-II)-infused mice. Effect of miR-25-3p on expression of fibrosis-related genes, including Col1a1, Col3a1, and Acta2, was investigated both in vitro and in vivo. MiR-25-3p was shown increased in the myocardium of Ang-II-infused mice and patients with heart failure. MiR-25-3p enhanced fibrosis-related gene expression in mouse cardiac fibroblasts (mCFs) and in the myocardium of Ang-II-infused mice. Dickkopf 3 (Dkk3) was identified as a target gene of miR-25-3p, and Dkk3 could ameliorate Smad3 activation and fibrosis-related gene expression via enhancing Smad7 expression in mCFs. Additionally, NF-κB signal was proven to mediate upregulation of miR-25-3p in cardiac fibrosis. Our findings suggest that miR-25-3p enhances cardiac fibrosis by suppressing Dkk3 to activate Smad3 and fibrosis-related gene expression.

Graphical abstract

中文翻译：

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Dickkopf 3：miR-25-3p 促进心肌纤维化中纤维化相关基因表达的新型靶基因

越来越多的证据表明 microRNA (miRNA) 参与了心脏纤维化。我们旨在阐明 miRNA miR-25-3p 对心脏纤维化的影响。miRNA 微阵列用于分析血管紧张素-II (Ang-II) 注入小鼠心肌中的 miRNA。在体外和体内研究了 miR-25-3p 对纤维化相关基因（包括 Col1a1、Col3a1 和 Acta2）表达的影响。MiR-25-3p 显示在注入 Ang-II 的小鼠和心力衰竭患者的心肌中增加。MiR-25-3p 增强了小鼠心脏成纤维细胞 (mCF) 和注入 Ang-II 的小鼠心肌中的纤维化相关基因表达。Dickkopf 3 (Dkk3) 被鉴定为 miR-25-3p 的靶基因，Dkk3 可以通过增强 mCFs 中 Smad7 的表达来改善 Smad3 的活化和纤维化相关基因的表达。此外，NF-κB 信号被证明在心脏纤维化中介导 miR-25-3p 的上调。我们的研究结果表明，miR-25-3p 通过抑制 Dkk3 以激活 Smad3 和纤维化相关基因表达来增强心脏纤维化。

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