缺血性心力衰竭中长链非编码RNA的失调
Long noncoding RNA dysregulation in ischemic heart failure.
作者信息
Greco Simona, Zaccagnini Germana, Perfetti Alessandra, Fuschi Paola, Valaperta Rea, Voellenkle Christine, Castelvecchio Serenella, Gaetano Carlo, Finato Nicoletta, Beltrami Antonio Paolo, Menicanti Lorenzo, Martelli Fabio
机构信息
IRCCS Policlinico San Donato, Via Morandi, 30, 20097, San Donato Milanese, Milan, Italy.
Goethe University, Frankfurt, Germany.
出版信息
J Transl Med. 2016 Jun 18;14(1):183. doi: 10.1186/s12967-016-0926-5.
BACKGROUND
Long noncoding RNAs (lncRNAs) are non-protein coding transcripts regulating a variety of physiological and pathological functions. However, their implication in heart failure is still largely unknown. The aim of this study is to identify and characterize lncRNAs deregulated in patients affected by ischemic heart failure.
METHODS
LncRNAs were profiled and validated in left ventricle biopsies of 18 patients affected by non end-stage dilated ischemic cardiomyopathy and 17 matched controls. Further validations were performed in left ventricle samples derived from explanted hearts of end-stage heart failure patients and in a mouse model of cardiac hypertrophy, obtained by transverse aortic constriction. Peripheral blood mononuclear cells of heart failure patients were also analyzed. LncRNA distribution in the heart was assessed by in situ hybridization. Function of the deregulated lncRNA was explored analyzing the expression of the neighbor mRNAs and by gene ontology analysis of the correlating coding transcripts.
RESULTS
Fourteen lncRNAs were significantly modulated in non end-stage heart failure patients, identifying a heart failure lncRNA signature. Nine of these lncRNAs (CDKN2B-AS1/ANRIL, EGOT, H19, HOTAIR, LOC285194/TUSC7, RMRP, RNY5, SOX2-OT and SRA1) were also confirmed in end-stage failing hearts. Intriguingly, among the conserved lncRNAs, h19, rmrp and hotair were also induced in a mouse model of heart hypertrophy. CDKN2B-AS1/ANRIL, HOTAIR and LOC285194/TUSC7 showed similar modulation in peripheral blood mononuclear cells and heart tissue, suggesting a potential role as disease biomarkers. Interestingly, RMRP displayed a ubiquitous nuclear distribution, while H19 RNA was more abundant in blood vessels and was both cytoplasmic and nuclear. Gene ontology analysis of the mRNAs displaying a significant correlation in expression with heart failure lncRNAs identified numerous pathways and functions involved in heart failure progression.
CONCLUSIONS
These data strongly suggest lncRNA implication in the molecular mechanisms underpinning HF.
背景
长链非编码RNA（lncRNA）是一类非蛋白质编码转录本，可调节多种生理和病理功能。然而，它们在心力衰竭中的作用仍 largely 未知。本研究的目的是鉴定和表征在缺血性心力衰竭患者中失调的 lncRNA。
方法
对 18 例非终末期扩张型缺血性心肌病患者和 17 例匹配对照的左心室活检组织进行 lncRNA 分析和验证。在终末期心力衰竭患者的心脏移植左心室样本以及通过主动脉缩窄获得的心脏肥大小鼠模型中进行进一步验证。还分析了心力衰竭患者的外周血单核细胞。通过原位杂交评估 lncRNA 在心脏中的分布。通过分析相邻 mRNA 的表达以及对相关编码转录本进行基因本体分析来探索失调 lncRNA 的功能。
结果
在非终末期心力衰竭患者中，有 14 种 lncRNA 受到显著调节，确定了心力衰竭 lncRNA 特征。其中 9 种 lncRNA（CDKN2B-AS1/ANRIL、EGOT、H19、HOTAIR、LOC285194/TUSC7、RMRP、RNY5、SOX2-OT 和 SRA1）在终末期衰竭心脏中也得到证实。有趣的是，在保守的 lncRNA 中，h19、rmrp 和 hotair 在心脏肥大小鼠模型中也被诱导。CDKN2B-AS1/ANRIL、HOTAIR 和 LOC285194/TUSC7 在外周血单核细胞和心脏组织中表现出相似的调节，表明它们作为疾病生物标志物的潜在作用。有趣的是，RMRP 显示出普遍的核分布，而 H19 RNA 在血管中更丰富，且在细胞质和细胞核中均有分布。对与心力衰竭 lncRNA 表达显著相关的 mRNA 进行基因本体分析，确定了许多参与心力衰竭进展的途径和功能。
结论
这些数据强烈表明 lncRNA 参与了心力衰竭的分子机制。
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