Long noncoding RNA Chast promotes cardiac remodeling
Long noncoding RNA Chast promotes cardiac remodeling
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DOI：
10.1126/scitranslmed.aaf1475
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发表时间：
2016-02-17
影响因子：
17.1
通讯作者：
Thum, Thomas
中科院分区：
文献类型：
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作者：
Viereck, Janika;Kumarswamy, Regalla;Thum, Thomas
最近的研究强调长非编码 RNA (lncRNA) 在心脏发育中发挥重要作用。然而，对 lncRNA 在心脏病中的了解仍然有限。整体lncRNA表达谱表明，在压力超负荷诱导的小鼠心脏肥大期间，一些lncRNA转录物失调。使用严格的选择标准，我们将Chast（心脏肥大相关转录本）确定为影响心肌细胞肥大的潜在lncRNA候选者。细胞分级分离实验表明，在横主动脉缩窄 (TAC) 手术的小鼠体内，Chast 在心肌细胞中特异性上调。与此相一致的是，人类的CHAST同系物在主动脉瓣狭窄患者的肥厚心脏组织中以及在肥厚刺激下的人胚胎干细胞衍生的心肌细胞中显着上调。 Chast 的病毒过度表达足以在体外和体内诱导心肌细胞肥大。 GapmeR 介导的 Chast 沉默可以预防和减弱 TAC 诱导的病理性心脏重塑，并且没有毒理学副作用的早期迹象。从机制上讲，Chast 负向调节含有 Pleckstrin 同源结构域的蛋白家族 M 成员 1（Chast 的相反链），阻碍心肌细胞自噬并驱动肥大。这些结果表明 Chast 可能是预防心脏重塑的潜在靶点，并强调了 lncRNA 在心脏病中的一般作用。
Recent studies highlighted long noncoding RNAs (lncRNAs) to play an important role in cardiac development. However, understanding of lncRNAs in cardiac diseases is still limited. Global lncRNA expression profiling indicated that several lncRNA transcripts are deregulated during pressure overload-induced cardiac hypertrophy in mice. Using stringent selection criteria, we identified Chast (cardiac hypertrophy-associated transcript) as a potential lncRNA candidate that influences cardiomyocyte hypertrophy. Cell fractionation experiments indicated that Chast is specifically up-regulated in cardiomyocytes in vivo in transverse aortic constriction (TAC)-operated mice. In accordance, CHAST homolog in humans was significantly up-regulated in hypertrophic heart tissue from aortic stenosis patients and in human embryonic stem cell-derived cardiomyocytes upon hypertrophic stimuli. Viral-based overexpression of Chast was sufficient to induce cardiomyocyte hypertrophy in vitro and in vivo. GapmeR-mediated silencing of Chast both prevented and attenuated TAC-induced pathological cardiac remodeling with no early signs on toxicological side effects. Mechanistically, Chast negatively regulated Pleckstrin homology domain-containing protein family M member 1 (opposite strand of Chast), impeding cardiomyocyte autophagy and driving hypertrophy. These results indicate that Chast can be a potential target to prevent cardiac remodeling and highlight a general role of lncRNAs in heart diseases.