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.

中文翻译：

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Lnc-Ang362是促纤维化的长非编码RNA，可通过抑制Smad7促进心肌梗死后的心脏纤维化。

背景技术心肌梗塞（MI）后的心脏纤维化导致心脏重塑和功能障碍。Smad7的失调负调节促纤维化转化生长因子-β1（TGF-β1）/ Smad信号转导促进了心脏纤维化。然而，TGF-β1/ Smad7失调的潜在分子机制仍然难以捉摸。长的非编码RNA（lncRNA）最近新兴成为心脏病的重要调节剂。在这里，我们报告lnc-Ang362是一种新型的lncRNA，它通过TGF-β1/ Smad7信号通路介导MI诱导的纤维化。方法和结果通过人工冠状动脉闭塞法建立了大鼠MI模型。微阵列分析鉴定了在MI心脏与假手术组之间在MI后4周差异表达的215个lncRNA（倍数变化> 2.0，P <0.05）。Lnc-Ang362具有最高的倍数上调，并且通过逆转录聚合酶链反应证实了该变化。同样，MI导致TGF-β1和胶原I / III表达显着增加，但显着下调Smad7表达。用TGF-β1处理的成年大鼠心脏成纤维细胞（RCF）显示lnc-Ang362表达增加而Smad7表达减少。此外，小干扰RNA导致lnc-Ang362的过表达和敲低分别降低和增加了Smad7表达。重要的是，该结果与RCF中胶原蛋白I / III的表达呈负相关。此外，荧光素酶报告基因测定证实Smad7是经过验证的lnc-Ang362靶标。进一步沉默Smad7减弱了lnc-Ang362敲低对RCF中胶原蛋白I / III表达降低的影响。结论这些结果表明，lnc-Ang362通过直接抑制Smad7促进心肌梗死后心肌纤维化，这可能会降低TGF-β1/ Smad信号通路的抑制性反馈调节。因此，lnc-Ang362可能是MI后心脏纤维化调节中的新型纤维化lncRNA。