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

Abstract 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.