Long noncoding RNA dysregulation in ischemic heart failure.
Long noncoding RNA dysregulation in ischemic heart failure.
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DOI：
10.1186/s12967-016-0926-5
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发表时间：
2016-06-18
影响因子：
7.4
通讯作者：
Martelli F
中科院分区：
文献类型：
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作者：
Greco S;Zaccagnini G;Perfetti A;Fuschi P;Valaperta R;Voellenkle C;Castelvecchio S;Gaetano C;Finato N;Beltrami AP;Menicanti L;Martelli F
长链非编码RNA（longnoncodingRNA，lncRNA）是一类非蛋白质编码的转录本，参与多种生理和病理功能的调控。然而，它们在心力衰竭中的意义在很大程度上仍然未知。本研究的目的是鉴定和表征缺血性心力衰竭患者中失调的lncRNA。在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中分析和验证了LncRNA。在来自终末期心力衰竭患者心脏的左心室样品和通过横向主动脉缩窄获得的心脏肥大小鼠模型中进行了进一步验证。同时分析心力衰竭患者外周血单个核细胞。通过原位杂交评估LncRNA在心脏中的分布。通过分析相邻mRNA的表达和相关编码转录本的基因本体分析来探索去调节的lncRNA的功能。在非终末期心力衰竭患者中，14种lncRNA被显著调节，鉴定了心力衰竭lncRNA特征。这些lncRNA中的9种（CDKN2B-AS1/ANRIL、EGOT、H19、HOTAIR、L0C285194/TUSC7、RMRP、RNY5、S0X2 - 0T和SRA1）也在终末期衰竭心脏中得到证实。有趣的是，在保守的lncRNA中，h19，rmrp和hotair也在心脏肥大的小鼠模型中诱导。CDKN 2B-AS 1/ANRIL、HOTAIR和LOC285194/TUSC 7在外周血单核细胞和心脏组织中显示出类似的调节作用，表明其作为疾病生物标志物的潜在作用。有趣的是，RMRP显示出无处不在的核分布，而H19 RNA在血管中更丰富，并且是细胞质和细胞核。显示与心力衰竭lncRNA表达显著相关的mRNA的基因本体分析鉴定了参与心力衰竭进展的许多途径和功能。这些数据强烈表明lncRNA在HF基础的分子机制中的作用。本文的在线版本（doi：10.1186/s12967 - 016 - 0926 - 5）包含补充材料，可供授权用户使用。
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. 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. 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. These data strongly suggest lncRNA implication in the molecular mechanisms underpinning HF. The online version of this article (doi:10.1186/s12967-016-0926-5) contains supplementary material, which is available to authorized users.