Sun Min, Yu Haiyi, Zhang Youyi, Li Zijian, Gao Wei
Department of Cardiology, Peking University Third Hospital and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research Beijing 100191, China.
Sci Rep. 2015 Dec 22;5:18351. doi: 10.1038/srep18351.
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.
β-肾上腺素能受体（β-ARs）的作用可诱导心脏成纤维细胞（CF）增殖及胶原蛋白合成，是多种疾病所致心脏纤维化的主要来源。最近发现，微小RNA-214（miR-214）在心脏重塑的发病机制中起重要作用。在本研究中，我们检测了miR-214在异丙肾上腺素（ISO，一种β-AR激动剂）诱导的CF增殖及胶原蛋白合成中的作用及其潜在机制。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CFs的增殖及胶原蛋白合成。通过生物信息学分析和荧光素酶测定，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）被确定为miR-214的直接靶基因；蛋白质印迹分析证实了这一结果。此外，与miR-214的上调相对应，纤维化心脏和成纤维细胞中Mfn2的表达下调。此外，miR-214的下调抑制了ISO处理诱导的ERK1/2 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。
