S1UTRSP5, a short restructured RNA from SLIT1 3′UTR, mitigates mouse cardiac remodeling via enhancing SlRT1 activity
Abstract
The 3′ untranslated regions (3′UTRs) have been known to regulate mRNA location, stability, and translation. 3′UTR length regulation is involved in the pathogenesis of cardiac dysfunction; however, more about the roles of 3′UTRs in cardiac remodeling remains elusive. In this study, we found slit guidance ligand 1 (SLIT1) 3′UTR with 3074 nt in length, which was 10-fold higher than SLIT1 coding sequence (CDS), was significantly decreased in the myocardium of patients with heart failure (HF) (n = 40) in comparison with healthy organ donors (n=17). We revealed that SLIT1 3′UTR and the 1526 nt fragment of SLIT1 3′UTR (FS1UTR) mainly and specifically combined miR-34a-5p, and improved cardiac remodeling through the miR-34a-5p/SIRT1 axis independently of Slit1 expression. Furthermore, a 260 nt restructured RNA derived from FS1UTR, S1UTRSP5, which contains 5 binding sites of miR-34a-5p seed sequence, alleviated cardiac remodeling in vitro and in vivo. We demonstrated that S1UTRSP5 blocked the function of miR-34a-5p and activated the SIRT1-PGC-1α-Nrf2 axis in cardiomyocytes, and promoted the SIRT1/Smad3 signal in cardiac fibroblasts and the SIRT1-eNOS-VEGFA axis in endothelial cells, collectively contributing to the amelioration of cardiac remodeling. These results provide new insights into the development of S1UTRSP5 as a novel inhibitor of miR-34a-5p for cardiac remodeling and HF.
Keywords:
cardiac remodeling; microRNAs; 3′ untranslated region; SIRT1; human cardiac organoid