长链非编码 RNA PVT1 通过 miR-128-3p-SP1-TGF-β1-Smad 轴调控心房颤动中的心房纤维化。

LncRNA PVT1 regulates atrial fibrosis via miR-128-3p-SP1-TGF-β1-Smad axis in atrial fibrillation.

机构信息

Department of Cardiology, Renmin Hospital of Wuhan University, NO.99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China.

Cardiovascular Research Institute, Wuhan University, Wuchang District, Wuhan, 430072, China.

出版信息

Mol Med. 2019 Mar 20;25(1):7. doi: 10.1186/s10020-019-0074-5.

BACKGROUND

Long non-coding RNAs (lncRNA) plasmacytoma variant translocation 1 (PVT1) has been shown to be associated with liver fibrosis. Nevertheless, the role of PVT1 in atrial fibrosis remains undefined. This study aims to elucidate the pathophysiological role of lncRNA PVT1 in the regulation of atrial fibrosis and to explore the underlying mechanism.

METHODS

Expression of PVT1, miR-128-sp, and Sp1 were examined in human atrial muscle tissues and angiotensin-II (Ang-II)-induced human atrial fibroblasts. Furthermore, the role of PVT1 in regulating atrial fibrosis in Ang-II-treated human atrial fibroblasts and Ang-II-induced atrial fibrosis in mice was investigated. Moreover, the interaction among PVT1, miR-128-3p, and Sp1 were examined using bioinformatics, expression correlation analysis, gain- or loss-of-function assays, RIP assays, and luciferase reporter assays. The involvement of transforming growth factor beta 1 (TGF-β1)/Smad pathway in this process was also explored.

RESULTS

PVT1 was increased in atrial muscle tissues from AF patients and positively with collagen I and collagen III. In vitro assay revealed that PVT1 overexpression facilitated the Ang-II-induced atrial fibroblasts proliferation, collagen production, and TGF-β1/Smad signaling activation, whereas PVT1 knockdown caused the opposite effect. In vivo assay further confirmed that PVT1 knockdown attenuated the Ang-II-induced mouse atrial fibrosis. Mechanically, PVT1 acted as a sponge for miR-128-3p to facilitate Sp1 expression, thereby activating the TGF-β1/Smad signaling pathway.

CONCLUSION

LncRNA PVT1 promotes atrial fibrosis via miR-128-3p-SP1-TGF-β1-Smad axis in atrial fibrillation.

背景

长链非编码 RNA（lncRNA）浆细胞瘤变异易位 1（PVT1）已被证明与肝纤维化有关。然而，PVT1 在心房纤维化中的作用仍未确定。本研究旨在阐明 lncRNA PVT1 在调节心房纤维化中的病理生理作用，并探讨其潜在机制。

方法

检测人心房肌组织和血管紧张素-II（Ang-II）诱导的人心房成纤维细胞中 PVT1、miR-128-sp 和 Sp1 的表达。进一步研究 PVT1 在 Ang-II 处理的人心房成纤维细胞中调节心房纤维化和 Ang-II 诱导的小鼠心房纤维化中的作用。此外，使用生物信息学、表达相关性分析、增益或缺失功能测定、RIP 测定和荧光素酶报告基因测定来检测 PVT1、miR-128-3p 和 Sp1 之间的相互作用。还探讨了转化生长因子β1（TGF-β1）/Smad 通路在此过程中的参与。

结果

PVT1 在房颤患者的心房肌组织中增加，并与胶原 I 和胶原 III 呈正相关。体外试验表明，PVT1 过表达促进 Ang-II 诱导的人心房成纤维细胞增殖、胶原产生和 TGF-β1/Smad 信号激活，而 PVT1 敲低则产生相反的效果。体内试验进一步证实，PVT1 敲低可减轻 Ang-II 诱导的小鼠心房纤维化。机制上，PVT1 作为 miR-128-3p 的海绵体促进 Sp1 表达，从而激活 TGF-β1/Smad 信号通路。