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-β I. Chromatin immunoprecipitation showed that further induction of Mmp-2 expression by transforming growth factor-β 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.

原理：心脏成纤维细胞（CF）在压力超负荷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非编码RNA（lncRNA）在心脏病理中的作用。然而，有关调控CF生物学并描述其在心脏重塑中的作用的lncRNA的详细报道仍然缺失。

目的：在这里，我们旨在表征慢性压力超负荷后鼠CF中lncRNA的表达，以鉴定富含CF的lncRNA，并研究其功能及其对心脏纤维化和舒张功能障碍的作用。

方法和结果：全局lncRNA分析鉴定出了几种失调的转录本。其中，lncRNA母本表达的基因3（ Meg3）被发现主要由CFs表达，并在晚期心脏重塑期间经历转录下调。在体外， Meg3调节基质金属蛋白酶2（MMP-2）的产生。的间隔聚体介导的沉默MEG3中的CF导致的下调MMP -2转录，这反过来，都在不存在和在变换的存在依赖于p53活性生长因子βI.染色质免疫沉淀表明，进一步感应转化生长因子-βI对Mmp -2表达的抑制被通过抑制Mmp -2启动子上的P53结合使Meg3沉默。一致地，横向主动脉缩窄后体内对Meg3的抑制作用阻止了心脏MMP-2的诱导，从而导致心脏纤维化的减少和舒张功能的改善。

结论：总的来说，我们的发现揭示了Meg3在体外和体内CFs调节MMP-2产生中的关键作用，确定了心脏纤维化发展的新参与者和潜在的预防心脏重塑的新靶标。