Luo Bihui, He Zhiyu, Huang Shijun, Wang Jinping, Han Dunzheng, Xue Hao, Liu Peiying, Zeng Xiaojun, Lu Dongfeng
Department of Cardiovascular Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangdong, China.
Department of Cardiovascular Medicine, Yue Bei People's Hospital, Guangdong, China.
Front Pharmacol. 2020 Dec 16;11:585680. doi: 10.3389/fphar.2020.585680. eCollection 2020.
Cardiac fibrosis is observed in nearly every form of myocardial disease. Long non-coding RNAs (lncRNAs) have been shown to play an important role in cardiac fibrosis, but the detailed molecular mechanism remains unknown. We aimed at characterizing lncRNA 554 expression in murine cardiac fibroblasts (CFs) after myocardial infarction (MI) to identify CF-enriched lncRNA and investigate its function and contribution to cardiac fibrosis and function. In this study, we identified lncRNA NONMMUT022554 (lncRNA 554) as a regulator of MI-induced cardiac fibrosis. We found that lncRNA 554 was significantly up-regulated in the mouse hearts following MI. Further study showed that lncRNA 554 was predominantly expressed in cardiac fibroblasts, indicating a potential role of lncRNA 554 in cardiac fibrosis. knockdown of lncRNA 554 by siRNA suppressed fibroblasts migration and expression of extracellular matrix (ECM); while overexpression of lncRNA 554 promoted expression of ECM genes. Consistently, lentivirus mediated knockdown of lncRNA 554 could inhibit cardiac fibrosis and improve cardiac function in mouse model of MI. More importantly, TGF-β1 inhibitor (TEW-7197) could reverse the pro-fibrotic function of lncRNA 554 in CFs. This suggests that the effects of lncRNA 554 on cardiac fibrosis is TGF-β1 dependent. Collectively, our study illustrated the role of lncRNA 554 in cardiac fibrosis, suggested that lncRNA 554 might be a novel target for cardiac fibrosis.
几乎在每种心肌疾病中都能观察到心脏纤维化。长链非编码RNA（lncRNAs）已被证明在心脏纤维化中起重要作用，但其详细的分子机制仍不清楚。我们旨在表征lncRNA 554在心肌梗死（MI）后小鼠心脏成纤维细胞（CFs）中的表达，以鉴定富含CF的lncRNA，并研究其对心脏纤维化和功能的作用及贡献。在本研究中，我们鉴定出lncRNA NONMMUT022554（lncRNA 554）是MI诱导的心脏纤维化的调节因子。我们发现lncRNA 554在MI后的小鼠心脏中显著上调。进一步研究表明，lncRNA 554主要在心脏成纤维细胞中表达，表明lncRNA 554在心脏纤维化中具有潜在作用。通过siRNA敲低lncRNA 554可抑制成纤维细胞迁移和细胞外基质（ECM）的表达；而lncRNA 554的过表达促进了ECM基因的表达。一致地，慢病毒介导的lncRNA 554敲低可抑制MI小鼠模型中的心脏纤维化并改善心脏功能。更重要的是，TGF-β1抑制剂（TEW-7197）可逆转lncRNA 554在CFs中的促纤维化功能。这表明lncRNA 554对心脏纤维化的作用是TGF-β1依赖性的。总的来说，我们的研究阐明了lncRNA 554在心脏纤维化中的作用，表明lncRNA 554可能是心脏纤维化的一个新靶点。
