Cardiac hypertrophy and dysfunction induced by overexpression of miR-214 in vivo
Cardiac hypertrophy and dysfunction induced by overexpression of miR-214 in vivo
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DOI：
10.1016/j.jss.2014.06.044
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发表时间：
2014-12-01
影响因子：
2.2
通讯作者：
Ni, Yiming
中科院分区：
文献类型：
--
作者：
Yang, Tao;Gu, Haihua;Ni, Yiming
背景资料：越来越多的研究表明microRNA在心肌肥厚和功能障碍的发病机制中起着关键作用。本研究评估了miR-214是否在心肌肥厚和心力衰竭的发展中起关键作用。方法：在人体组织中，miR-214过表达被确定为促进心肌肥厚。利用生物信息学数据库预测miR-214的直接靶点，并利用荧光素酶双报告系统进行验证。我们沉默miR-214在压力超负荷小鼠模型的心脏failure.Results：心肌细胞特异性过表达的miR-214的转基因小鼠的分析表明，他们的心脏比野生型心脏重21%，并表达与扩张型心肌病一致的几个生化和功能标志物。这些发现包括左心室内径增大、室壁变薄、射血分数降低、缩短分数和胎儿基因表达增加。zeste同源物2增强子（EZH 2）被证实是心肌细胞中miR-214的直接靶点。在体内沉默的miR-214使用一个特定的EZH 2救援心脏EZH 2的表达，并防止心脏肥大和dysfunctions.Conclusions：总的来说，这些结果表明，miR-214可能诱导病理性心脏肥大的一部分，通过减少EZH 2信使RNA水平。因此，miR-214可能是治疗某些心脏疾病状态的潜在治疗靶点。(C)2014 Elsevier Inc. All rights reserved.
Background: An increasing number of studies have demonstrated the critical role of microRNAs in the pathogenesis of cardiac hypertrophy and dysfunction. This study evaluated whether miR-214 plays a pivotal role in the development of cardiac hypertrophy and heart failure.Methods: In human tissues, miR-214 overexpression was determined to promote cardiac hypertrophy. We predicted miR-214 direct target by bioinformatics database and verifed it using luciferase dual reporting system. We silenced miR-214 using a specific antagomir in a pressure-overload mouse model of heart failure.Results: Analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-214 indicated that their hearts were 21% heavier than wild-type hearts and expressed several biochemical and functional markers consistent with dilated cardiomyopathy. These findings include enlarged left ventricular internal diameters, wall thinning, reduced ejection fraction, fractional shortening, and an increased fetal gene expression. The enhancer of zeste homolog 2 (EZH2) was confirmed as a direct target of miR-214 in cardiomyocytes. In vivo silencing of miR-214 using a specific antagomir rescued cardiac EZH2 expression and prevented cardiac hypertrophy and dysfunction.Conclusions: Taken together, these results suggest that miR-214 may induce pathologic cardiac hypertrophy in part by reducing EZH2 messenger RNA levels. MiR-214 may therefore be a potential therapeutic target for treating certain cardiac disease states. (C) 2014 Elsevier Inc. All rights reserved.