Lnc-Ang362 is a pro-fibrotic long non-coding RNA promoting cardiac fibrosis after myocardial infarction by suppressing Smad7

Abstract

Background: Cardiac fibrosis following myocardial infarction (MI) leads to cardiac remodeling and dysfunction. Dysregulation of Smad7 which negatively regulates the profibrotic transforming growth factor-β1 (TGF-β1)/Smad signaling promotes cardiac fibrosis. However, the molecular mechanisms underlying TGF-β1/Smad7 dysregulation remain elusive. Long non-coding RNAs (lncRNAs) are recently emerging as important regulators of cardiac diseases. Here, we report lnc-Ang362 is a novel lncRNA mediating MI-induced fibrosis through TGF-β1/Smad7 signaling pathway.

Methods and results: The MI model was established by artificial coronary artery occlusion in rats. Microarray analysis identified 215 lncRNAs (fold change > 2.0, P < 0.05) differentially expressed between MI hearts and the sham group 4 weeks after MI. Lnc-Ang362 had the highest fold upregulation and the change was validated by reverse transcription polymerase chain reaction. Also, MI caused a marked increase in TGF-β1 and collagen I/III expression, but significantly downregulated Smad7 expression. Adult rat cardiac fibroblasts (RCFs) treated with TGF-β1 showed increased lnc-Ang362 expression and decreased Smad7 expression. Moreover, overexpression and knockdown of lnc-Ang362 by small interfering RNAs reduced and increased Smad7 expression, respectively. Importantly, this result was negatively correlated with the expression of collagen I/III in RCFs. Furthermore, the luciferase reporter assays confirmed that Smad7 was a validated lnc-Ang362 target. Further silencing Smad7 attenuated the effects of lnc-Ang362 knockdown on decreasing collagen I/III expression in RCFs.

Conclusions: These results suggested lnc-Ang362 promoted cardiac fibrosis after MI via directly suppressing Smad7, which may decrease the inhibitory feedback regulation of TGF-β1/Smad signaling pathway. Thus, lnc-Ang362 may be a novel profibrotic lncRNA in the regulation of cardiac fibrosis post MI.

Keywords: Cardiac fibrosis; Long non-coding RNA; Myocardial infarction; Smad7; Transforming growth factor-β1.