Circ_LAS1L regulates cardiac fibroblast activation, growth, and migration through miR-125b/SFRP5 pathway
Circ_LAS1L regulates cardiac fibroblast activation, growth, and migration through miR-125b/SFRP5 pathway
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Circ_LAS1L通过miR-125b/SFRP5途径调节心脏成纤维细胞的激活、生长和迁移
DOI：
10.1002/cbf.3486
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发表时间：
2020-01-16
影响因子：
3.6
通讯作者：
Bie, Zi-dong
中科院分区：
文献类型：
--
作者：
Sun, Li-ye;Zhao, Jin-chao;Bie, Zi-dong
目前的研究表明，环状RNA（circRNA）和微小RNA（miRNA）在急性心肌梗死（AMI）中密切相关。既往研究表明miR-125b促进心脏成纤维细胞（CF）纤维化和上调，进一步实验表明circ_LAS1L具有多个miR-125b结合位点，且其表达在AMI患者和CF中呈负相关。 RNA 免疫沉淀 (RIP)、pull down 和双荧光素酶报告基因测定均证实 miR-125b 直接与 circ_LAS1L 结合。 Circ_LAS1L过表达促进下游靶基因分泌型卷曲相关蛋白5（SFRP5）的表达，抑制α-SMA、I型胶原和III型胶原的表达，抑制CF增殖和迁移，促进细胞凋亡。当circ_LAS1L过表达载体和miR-125b模拟物共转染时，上述基因表达和CF生物学行为没有明显变化。但当circ_LAS1L过表达载体与SFRP5 siRNA共转染时，SFRP5表达仍下调，α-SMA、I型胶原和III型胶原表达上调，CFs增殖和迁移增加。因此，circ_LAS1L通过吸附miR-125b来抑制其活性，从而促进SFRP5的表达，进而调节CF的生物学特性。这些发现可能为心肌梗死后心肌纤维化的调控提供重要的实验依据。研究意义 研究表明，环状RNA（circRNA）在心血管疾病中发挥重要作用，但对其在心肌纤维化过程中的作用研究较少。在本研究中，我们发现circ_LAS1L在急性心肌梗死（AMI）患者和心脏成纤维细胞（CF）中表达下调，并且能够直接与miR-125b结合，从而促进下游靶基因分泌型卷曲相关蛋白5（SFRP5）的表达，最终抑制CF的激活、增殖和迁移，促进细胞凋亡。这就提示circ_LAS1L/miR-125b/SFRP5通路能够调节CF的生物学功能,可能在心肌纤维化过程中发挥重要作用,从而为心肌梗死后心肌纤维化的调控提供重要的理论依据。
Current studies have shown that circular RNAs (circRNAs) and microRNAs (miRNAs) are closely related in acute myocardial infarction (AMI). Previous studies have shown that miR-125b promotes fibrosis and up-regulates in cardiac fibroblasts (CFs), and further experiments showed that circ_LAS1L had multiple binding sites of miR-125b, and their expression was inversely related in AMI patients and CFs. RNA immunoprecipitation (RIP), pull down, and dual luciferase reporter gene assay all confirmed that miR-125b directly bound to circ_LAS1L. Circ_LAS1L overexpression promoted the expression of downstream target gene secreted frizzled-related protein 5 (SFRP5), inhibited the expression of alpha-SMA, collagen I, and collagen III, inhibited CF proliferation and migration, and promoted apoptosis. When cotransfected with circ_LAS1L overexpression vector and miR-125b mimics, the above gene expression and CF biological behaviours did not change significantly. But when cotransfected with circ_LAS1L overexpression vector and SFRP5 siRNA, SFRP5 expression was still down-regulated, the expression of alpha-SMA, collagen I, and collagen III was up-regulated, and the proliferation and migration of CFs were increased. Therefore, circ_LAS1L inhibits the activity of miR-125b by adsorbing it, thus promoting the expression of SFRP5 and then regulating the biological characteristics of CFs. These findings may provide an important experimental basis for the regulation of myocardial fibrosis after myocardial infarction. Significance of the study Studies have shown that circular RNAs (circRNAs) play important roles in cardiovascular diseases, but there are few studies on their roles in the process of myocardial fibrosis. In this study, we found that circ_LAS1L was down-regulated in acute myocardial infarction (AMI) patients and cardiac fibroblasts (CFs), and could bind directly to miR-125b, thereby promoting the expression of downstream target gene secreted frizzled-related protein 5 (SFRP5), ultimately inhibiting the activation, proliferation and migration of CF, and promoting apoptosis. This suggests that circ_LAS1L/miR-125b/SFRP5 pathway can regulate the biological function of CF and may play an important role in the process of myocardial fibrosis, thus providing an important theoretical basis for the regulation of myocardial fibrosis after myocardial infarction.