长链非编码 RNA Ang362 通过抑制 Smad7 促进心肌梗死后的心肌纤维化。
Lnc-Ang362 is a pro-fibrotic long non-coding RNA promoting cardiac fibrosis after myocardial infarction by suppressing Smad7.
机构信息
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
出版信息
Arch Biochem Biophys. 2020 May 30;685:108354. doi: 10.1016/j.abb.2020.108354. Epub 2020 Mar 30.
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.
背景
心肌梗死后的心脏纤维化导致心脏重构和功能障碍。Smad7 的失调会负调控促纤维化的转化生长因子-β1（TGF-β1）/Smad 信号通路，从而促进心脏纤维化。然而，TGF-β1/Smad7 失调的分子机制仍不清楚。长链非编码 RNA（lncRNA）最近被认为是心脏疾病的重要调节因子。在这里，我们报告 lnc-Ang362 是一种通过 TGF-β1/Smad7 信号通路介导心肌梗死后纤维化的新型 lncRNA。
方法和结果
通过人工冠状动脉闭塞在大鼠中建立心肌梗死模型。微阵列分析鉴定出 215 个 lncRNA（倍数变化>2.0，P<0.05）在心肌梗死后 4 周时在 MI 心脏与假手术组之间差异表达。lnc-Ang362 的上调倍数最高，通过逆转录聚合酶链反应验证了这一变化。此外，MI 导致 TGF-β1 和胶原 I/III 的表达显著增加，但 Smad7 的表达明显降低。用 TGF-β1 处理的成年大鼠心肌成纤维细胞（RCFs）显示 lnc-Ang362 表达增加，Smad7 表达降低。此外，通过小干扰 RNA 进行 lnc-Ang362 的过表达和敲低分别减少和增加 Smad7 的表达。重要的是，这一结果与 RCFs 中胶原 I/III 的表达呈负相关。此外，荧光素酶报告基因实验证实 Smad7 是 lnc-Ang362 的一个验证靶点。进一步沉默 Smad7 可减弱 lnc-Ang362 敲低对 RCFs 中胶原 I/III 表达减少的影响。
结论
这些结果表明，lnc-Ang362 通过直接抑制 Smad7 促进心肌梗死后的心脏纤维化，这可能降低 TGF-β1/Smad 信号通路的抑制性反馈调节。因此，lnc-Ang362 可能是调节心肌梗死后心脏纤维化的一种新型促纤维化 lncRNA。
Zotero 插件