Department of Cardiology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, PR China.
Department of Cardiology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, PR China; Department of Endocrinology, The First Affiliated Hospital of Nanchang University, Nanchang, PR China.
Biochem Biophys Res Commun. 2020 Mar 26;524(1):169-177. doi: 10.1016/j.bbrc.2020.01.062. Epub 2020 Jan 23.
Cardiovascular diseases (CVDs) is the first cause of death worldwide, generally exhibiting a high morbidity, high disability rate and high mortality especially in the elderly persons (>50 years old). Previously, extensive studies have demonstrated that cardiac fibrosis plays cardinal roles in the pathogenesis of CVDs. However, due to the unclear underlying mechanisms of cardiac fibrosis, its clinical intervention remains very lacking. Long non-coding RNAs (lncRNAs), a class of non-coding RNA but differing from microRNAs, are generally considered as transcripts with a length ranging 200 to 100 nucleotides. Recently, accumulating evidence showed that lncRNAs involve in the pathogenesis of cardiac fibrosis. Fendrr (FOXF1 adjacent non-coding developmental regulatory RNA), is a spliced long non-coding RNA transcribed bi-directionally with FOXF1 on the opposite strand. Fendrr has been demonstrated to be essential for normal development of the heart and body wall in mouse, and shows a good anti-fibrotic activity in pulmonary fibrosis. In this study, we aimed to explore the effects of Fendrr on cardiac fibrosis. Intriguingly, we first observed that lncRNA Fendrr was up-regulated in the heart tissues of transverse aortic constriction (TAC) induced cardiac fibrosis mouse models, determined by RT-QPCR. Loss-function of Fendrr significantly alleviated the cardiac fibrosis phenotypes induced by TAC, indicating that Fendrr is required for the pathogenesis of cardiac fibrosis. In mechanism, we demonstrated experimentally that Fendrr directly targeting miR-106b, by which the lncRNA promotes cardiac fibrosis (indicated by the elevation of Col1a1, Col3a1, CTGF and ACTA2 expression) in a miR-106b mediated manner. Collectively, our findings highlight the axis of Fendrr/miR-106b/Samd3 in the pathogenesis of cardiac fibrosis, which may be a promising target for clinical intervention target of cardiac fibrosis.
心血管疾病（CVDs）是全球范围内的首要死因，普遍具有高发病率、高致残率和高死亡率的特点，尤其是在老年人（>50 岁）中。先前的广泛研究表明，心肌纤维化在 CVDs 的发病机制中起着关键作用。然而，由于心肌纤维化的潜在机制尚不清楚，其临床干预措施仍然非常缺乏。长链非编码 RNA（lncRNA）是一类不同于 microRNA 的非编码 RNA，通常被认为是长度在 200 到 100 个核苷酸之间的转录本。最近，越来越多的证据表明 lncRNA 参与了心肌纤维化的发病机制。Fendrr（FOXF1 相邻非编码发育调节 RNA）是一种拼接的长非编码 RNA，与 FOXF1 反义链双向转录。已经证明 Fendrr 在小鼠心脏和体壁的正常发育中是必不可少的，并且在肺纤维化中表现出良好的抗纤维化活性。在这项研究中，我们旨在探讨 Fendrr 对心肌纤维化的影响。有趣的是，我们首先通过 RT-QPCR 观察到，在横主动脉缩窄（TAC）诱导的心肌纤维化小鼠模型的心脏组织中，lncRNA Fendrr 上调。Fendrr 的功能丧失显著缓解了 TAC 诱导的心肌纤维化表型，表明 Fendrr 是心肌纤维化发病机制所必需的。在机制上，我们通过实验证明，Fendrr 通过直接靶向 miR-106b，从而促进心肌纤维化（通过 Col1a1、Col3a1、CTGF 和 ACTA2 表达的升高来指示），这是一种 miR-106b 介导的方式。总之，我们的研究结果强调了 Fendrr/miR-106b/Samd3 在心肌纤维化发病机制中的轴，这可能是心肌纤维化临床干预的一个有前途的靶点。
