Plasma exosomal miR-339-3p promotes myocardial remodeling in chronic heart failure by regulating USP25-mediated DDX58 deubiquitination.

To explore the mechanism by which plasma exosome miR-339-3p regulates myocardial remodeling in heart failure (HF). Plasma exosomes were isolated from 5 patients with HF and 5 controls, and cell uptake was determined by transmission electron microscopy, western blot and PKH26 labeling. Angiotensin II treated AC16 cells to induce cell hypertrophy. Cell counting kit-8 assay and flow cytometry were used to detect cell viability and apoptosis to evaluate the effect of HF-exo. High-throughput sequencing was performed on exosomal microRNAs to identify key differential mirnas (miR-339-3p), and database screening was used to verify downstream target proteins ubiquitin-specific protease 25 (USP25) by dual-luciferase reporter gene assay and reverse transcription-quantitative polymerase chain reaction/western blot. Searchtool for the retrieval of interacting genes, the Cancer Genome Atlas and co-immunoprecipitation were used to screen USP25-interacting proteins (DDX58). Analysis revealed that inhibition of miR-339-3p completely reversed cardiomyocyte injury induced by HF-exo. miR-339-3p directly targets USP25, down-regulates its expression, and impairs its K48-related DDX58 deubiquitination. Overexpression of USP25 can reverse myocardial injury induced by mir-339-3p, and DDX58 silencing can eliminate the protective effect of USP25. Plasma exosome miR-339-3p promotes myocardial remodeling in HF through the miR-339-3p-USP25-DDX58 axis and is a potential target for the diagnosis and treatment of HF.