Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy
Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy
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长非编码RNA将细胞外基质基因表达与缺血性心肌病联系起来
DOI：
10.1093/cvr/cvw201
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发表时间：
2016-11-01
影响因子：
10.8
通讯作者：
Wang, Da-Zhi
中科院分区：
文献类型：
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作者：
Huang, Zhan-Peng;Ding, Yan;Wang, Da-Zhi
心肌梗死引起的缺血性心肌病（ICM）是心力衰竭（HF）的主要原因。近年来，人们发现了数千种长链非编码RNA（lncRNA），它们参与了多种生物学过程。然而，大多数lncRNA在HF中的作用在很大程度上仍然未知。本研究的目的是验证lncRNA的表达和功能在病变心脏中受到差异调节的假设。在本研究中，我们对ICM患者（n = 15）和对照组（n = 15）的心脏样本中的蛋白质编码和非编码RNA进行了RNA深度测序。全基因组转录组分析证实，许多蛋白质编码基因先前已知的参与HF的改变，在ICM心脏。在ICM心脏中鉴定的145个差异表达的lncRNA中，我们发现了一组35个lncRNA，它们显示出强的正表达相关性。差异表达的lncRNA和蛋白质编码基因的表达相关系数分析揭示了lncRNA和细胞外基质（ECM）蛋白质编码基因之间的强关联。我们在心脏成纤维细胞中过表达或敲低选定的lncRNA，我们的结果表明lncRNA是纤维化和ECM合成基因表达的重要调节因子。此外，我们发现lncRNA参与TGF-β通路，调节ECM基因的表达和肌成纤维细胞分化。我们的研究表明，许多lncRNA的表达在ICM中受到动态调节。lncRNA在ICM发生发展过程中调节ECM的表达和功能，并参与心肌纤维化。我们的研究结果进一步表明，lncRNA可能代表新的心脏功能和心脏疾病，包括ICM的调节剂。
Ischemic cardiomyopathy (ICM) resulting from myocardial infarction is a major cause of heart failure (HF). Recently, thousands of long non-coding RNAs (lncRNAs) have been discovered and implicated in a variety of biological processes. However, the role of most lncRNAs in HF remains largely unknown. The aim of this study is to test the hypothesis that the expression and function of lncRNAs are differentially regulated in diseased hearts.In this study, we performed RNA deep sequencing of protein-coding and non-coding RNAs from cardiac samples of patients with ICM (n = 15) and controls (n = 15). Genome-wide transcriptome analysis confirmed that many protein-coding genes previously known to be involved in HF were altered in ICM hearts. Among the 145 differentially expressed lncRNAs identified in ICM hearts, we found a set of 35 lncRNAs that display strong positive expression correlation. Expression correlation coefficient analyses of differentially expressed lncRNAs and protein-coding genes revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. We overexpressed or knocked down selected lncRNAs in cardiac fibroblasts and our results suggest that lncRNAs are important regulators of fibrosis and the expression of ECM synthesis genes. Moreover, we show that lncRNAs participate in the TGF-beta pathway to modulate the expression of ECM genes and myofibroblast differentiation.Our studies demonstrate that the expression of many lncRNAs is dynamically regulated in ICM. lncRNAs regulate the expression and function of ECM and cardiac fibrosis during the development of ICM. Our results further indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ICM.