Inhibition of the Cardiac Fibroblast- Enriched lncRNA Meg3 Prevents Cardiac Fibrosis and Diastolic Dysfunction
Inhibition of the Cardiac Fibroblast- Enriched lncRNA Meg3 Prevents Cardiac Fibrosis and Diastolic Dysfunction
复制标题
DOI：
10.1161/circresaha.117.310624
复制
发表时间：
2017-08-18
影响因子：
20.1
通讯作者：
Thum, Thomas
中科院分区：
文献类型：
--
作者：
Piccoli, Maria-Teresa;Gupta, Shashi Kumar;Thum, Thomas
理由：心脏成纤维细胞（CFs）在压力过载后驱动细胞外基质重塑，导致纤维化和舒张功能障碍。最近的研究描述了长链非编码rna （lncRNAs）在心脏病理中的作用。然而，关于lncrna调节CF生物学和描述其在心脏重塑中的意义的详细报道仍然缺失。目的：在这里，我们旨在表征慢性压力过载后小鼠CFs中的lncRNA表达，以鉴定富含cf的lncRNA，并研究它们的功能及其在心脏纤维化和舒张功能障碍中的作用。方法和结果：全球lncRNA分析鉴定了几种失调转录物。其中lncRNA母系表达基因3 （Meg3）主要由CFs表达，并在心脏重构后期发生转录下调。在体外，Meg3调节基质金属蛋白酶-2 （MMP-2）的产生。gapmer介导的Meg3在CFs中的沉默导致Mmp-2转录下调，而Mmp-2转录又依赖于P53的活性，无论是否存在转化生长因子- β I。染色质免疫沉淀显示，通过抑制P53与Mmp-2启动子的结合，Meg3沉默阻断了转化生长因子- β I进一步诱导Mmp-2表达。同样，在横断主动脉收缩后，体内Meg3的抑制阻止了心脏MMP-2的诱导，导致心脏纤维化减少，舒张性能改善。总之，我们的研究结果揭示了Meg3在体外和体内调节CFs产生MMP-2中的关键作用，确定了心脏纤维化发展的新参与者和预防心脏重塑的潜在新靶点。
Rationale: Cardiac fibroblasts (CFs) drive extracellular matrix remodeling after pressure overload, leading to fibrosis and diastolic dysfunction. Recent studies described the role of long noncoding RNAs (lncRNAs) in cardiac pathologies. Nevertheless, detailed reports on lncRNAs regulating CF biology and describing their implication in cardiac remodeling are still missing.Objective: Here, we aimed at characterizing lncRNA expression in murine CFs after chronic pressure overload to identify CF-enriched lncRNAs and investigate their function and contribution to cardiac fibrosis and diastolic dysfunction.Methods and Results: Global lncRNA profiling identified several dysregulated transcripts. Among them, the lncRNA maternally expressed gene 3 (Meg3) was found to be mostly expressed by CFs and to undergo transcriptional downregulation during late cardiac remodeling. In vitro, Meg3 regulated the production of matrix metalloproteinase-2 (MMP-2). GapmeR-mediated silencing of Meg3 in CFs resulted in the downregulation of Mmp-2 transcription, which, in turn, was dependent on P53 activity both in the absence and in the presence of transforming growth factor-beta I. Chromatin immunoprecipitation showed that further induction of Mmp-2 expression by transforming growth factor-beta I was blocked by Meg3 silencing through the inhibition of P53 binding on the Mmp-2 promoter. Consistently, inhibition of Meg3 in vivo after transverse aortic constriction prevented cardiac MMP-2 induction, leading to decreased cardiac fibrosis and improved diastolic performance.Conclusions: Collectively, our findings uncover a critical role for Meg3 in the regulation of MMP-2 production by CFs in vitro and in vivo, identifying a new player in the development of cardiac fibrosis and potential new target for the prevention of cardiac remodeling.