Circ_LAS1L regulates cardiac fibroblast activation, growth, and migration through miR‐125b/SFRP5 pathway

Abstract

Funding informationThis work was supported by the young teachers program of Beijing university of Chinese medicine (2018-JYBZZ-JS094) and the scientific research project of Sichuan health committee (19PJ214).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. K E Y W O R D S cardiac fibroblast, circRNA, miR-125b, myocardial infarction, SFRP5 Li-ye Sun and Jin-chao Zhao contributed equally to this work.

Pivotal Role of TGF-β/Smad Signaling in Cardiac Fibrosis: Non-coding RNAs as Effectual Players

“…circRNAs miR-125b induces fibrotic process and upregulation in CFs, indicating numerous binding sites of miR-125b for circ_LAS1L, with inverse association of their expression in those with acute myocardial infarction (AMI) and CFs. RNA immunoprecipitation (RIP), pull-down, and dual-luciferase reporter gene assay supported direct binding of miR-125b bound to circ_LAS1L (114). Overexpressed Circ_LAS1L led to promotion of the downstream target gene secreted frizzledassociated protein 5 (SFRP5) expressions, while reducing α-SMA, collagen I, and collagen III expression; hindering CF proliferation and migration; and increasing apoptosis.…”

“…Sun et al investigated that circ_LAS1L in those suffering AMI and CFs was downregulated and was capable of direct binding to miR-125b, consequently enhancing the downstream target gene secreted frizzled-related protein 5 (SFRP5) expression, finally repressing CF activating, proliferating, and migrating, along with inducing apoptosis. Thus, it is has been posited that the circ_LAS1L/miR-125b/SFRP5 pathway is capable of modulating the biological characteristics of CF and can contribute vitally to the process of cardiac fibrosis, therefore offering a significant theoretical basis to regulate cardiac fibrotic event following myocardial infarction (114).…”

Circulating Circular RNAs: Novel Biomarkers for Heart Failure

“…Silencing circRNA 010567 in the rat model of acute MI established that using ligation of the left anterior descending coronary artery would improve cardiac function, higher ejection fraction, and fractional shortening and alleviate MF through the TGF-b1 signaling pathway (Bai et al, 2020). A cardioprotective circRNA, circ_LAS1L, was found markedly downregulated in acute MI (Sun L. Y. et al, 2020). Overexpression of circ_LAS1L could inhibit cardiac fibroblast proliferation and migration and promote apoptosis.…”

Rapid Development of Targeting circRNAs in Cardiovascular Diseases

“…[50][51][52][53] Additionally, studies from Sun et al elucidated that CF activation and proliferation can be regulated by cytoplasmic circLAS1L via the miR-125b/SFRP5 pathway. 54 These discoveries lead to the question whether exosomal circRNAs are also involved in CF activation and warrant further investigation. If exosomal circRNA is involved, novel therapeutic strategies could be developed by using artificial circRNA-enriched exosomes.…”