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. The human SLIT1 3'UTR or FS1UTR combines miR-34a-5p to increase SIRT1 level in CMs, CFs and ECs. Notably, S1UTRSP5, a 260-nt stable RNA derived from SLIT1 3'UTR, efficiently sponged miR-34a-5p to activate SIRT1-PGC-1α-Nrf2 pathway in CMs, and to promote SIRT1/Smad3 signal in CFs and the SIRT1-eNOS-VEGFA pathway in ECs, collectively contributing to amelioration of cardiac remodeling.
