MicroRNA-214 Mediates Isoproterenol-induced Proliferation and Collagen Synthesis in Cardiac Fibroblasts.
MicroRNA-214 Mediates Isoproterenol-induced Proliferation and Collagen Synthesis in Cardiac Fibroblasts.
复制标题
MicroRNA-214 介导异丙肾上腺素诱导的心脏成纤维细胞增殖和胶原蛋白合成。
DOI：
10.1038/srep18351
复制
发表时间：
2015-12-22
影响因子：
4.6
通讯作者：
Gao W
中科院分区：
文献类型：
--
作者：
Sun M;Yu H;Zhang Y;Li Z;Gao W
β-肾上腺素能受体（β-ARs）的激活会诱导心脏成纤维细胞（CF）增殖和胶原蛋白合成，是多种疾病所致心脏纤维化的主要原因。最近发现，微小核糖核酸 - 214（miR - 214）在心脏重塑的发病机制中发挥重要作用。在本研究中，我们探究了miR - 214在异丙肾上腺素（ISO，一种β-AR激动剂）诱导的CF增殖和胶原蛋白合成中的作用及潜在机制。在ISO介导的纤维化心脏组织和成纤维细胞中，miR - 214的表达均升高。拮抗剂下调miR - 214可减弱ISO处理的CF的增殖和胶原蛋白合成。通过生物信息学分析和荧光素酶报告基因实验，确定细胞增殖和组织纤维化的关键调节因子——线粒体融合蛋白2（Mfn2）是miR - 214的直接靶基因，蛋白质免疫印迹分析也证实了这一结果。此外，与miR - 214上调相对应，Mfn2在纤维化心脏和成纤维细胞中的表达下调。而且，下调miR - 214可抑制ISO处理诱导的细胞外信号调节激酶1/2（ERK1/2）丝裂原活化蛋白激酶（MAPK）信号通路的激活。总之，我们的研究表明，miR - 214通过抑制Mfn2和激活ERK1/2 MAPK信号通路来介导CF增殖和胶原蛋白合成，这为β-AR激活诱导心脏纤维化的机制提供了新的解释。
The action of β-adrenergic receptors (β-ARs) induces cardiac fibroblast (CF) proliferation and collagen synthesis and is a major source of the cardiac fibrosis caused by various diseases. Recently, microRNA-214 (miR-214) was found to play an important role in the pathogenesis of cardiac remodelling. In the present study, we examined the role and the underlying mechanism of miR-214 in isoproterenol (ISO, a β-AR agonist)-induced CF proliferation and collagen synthesis. The expression of miR-214 was increased in both ISO-mediated fibrotic heart tissue and fibroblasts. Downregulation of miR-214 by antagonists attenuated the proliferation and collagen synthesis in ISO-treated CFs. Using bioinformatics analysis and luciferase assays, mitofusin2 (Mfn2), a critical regulator of cell proliferation and tissue fibrosis, was identified as a direct target gene of miR-214; this result was confirmed by western blot analysis. Additionally, corresponding to the upregulation of miR-214, the expression of Mfn2 was downregulated in the fibrotic heart and fibroblasts. Furthermore, the downregulation of miR-214 inhibited the activation of ERK1/2 MAPK signalling induced by ISO treatment. In conclusion, our study demonstrated that miR-214 mediates CF proliferation and collagen synthesis via inhibition of Mfn2 and activation of ERK1/2 MAPK signalling, which provides a new explanation for the mechanism of β-AR activation-induced cardiac fibrosis.