Inhibition of the Cardiac Fibroblast-Enriched lncRNA Meg3 Prevents Cardiac Fibrosis and Diastolic Dysfunction
Rationale: Cardiac fibroblasts (CFs) drive extracellular matrix (ECM) remodeling following 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 following chronic pressure overload, in order 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 deregulated transcripts. Among them, the lncRNA 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 upon P53 activity both in the absence and in the presence of TGF-β I. Chromatin immunoprecipitation (ChIP) showed that further induction of Mmp-2 expression by TGF-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 (TAC) 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.
- Received January 12, 2017.
- Revision received June 13, 2017.
- Accepted June 18, 2017.