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Published on: April 10, 2019
Plasma exosomal miR-339-3p promotes myocardial remodeling in chronic heart failure by regulating USP25-mediated DDX58
Guoqiang Jing1, Ting Xu2, Yuhong Ma3
1Department of Cardiology Affiliated Hospital of Inner Mongolia Medical University Hohhot China.
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.
Insights
Plasma exosome miR-339-3p promotes heart failure (HF) myocardial remodeling by targeting USP25 and DDX58. Inhibiting miR-339-3p reversed cardiomyocyte injury, suggesting it as a potential diagnostic and therapeutic target for HF.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Exosome Biology
Background:
- Heart failure (HF) involves complex myocardial remodeling processes.
- Plasma exosomes and their microRNA cargo are implicated in intercellular communication during disease.
- Understanding the specific molecular mechanisms of exosome-mediated regulation in HF is crucial.
Purpose of the Study:
- To elucidate the role of plasma exosome miR-339-3p in regulating myocardial remodeling in heart failure (HF).
- To identify the molecular targets and pathways involved in exosome-mediated cardiac dysfunction.
Main Methods:
- Isolation and characterization of plasma exosomes from HF patients and controls.
- In vitro studies using Angiotensin II-treated AC16 cells to mimic HF conditions.
- High-throughput sequencing to identify differential exosomal microRNAs, focusing on miR-339-3p.
- Dual-luciferase reporter assays, RT-qPCR, and Western blotting to validate targets (USP25, DDX58).
- Co-immunoprecipitation and bioinformatic analyses to identify protein interactions.
Main Results:
- Plasma exosome miR-339-3p was identified as a key differential microRNA in HF.
- miR-339-3p directly targets ubiquitin-specific protease 25 (USP25), down-regulating its expression.
- USP25 regulates K48-related deubiquitination of DDX58.
- Inhibition of miR-339-3p reversed HF exosome-induced cardiomyocyte injury.
- Overexpression of USP25 or DDX58 silencing modulated cardiomyocyte injury, confirming the miR-339-3p-USP25-DDX58 axis.
Conclusions:
- Plasma exosome miR-339-3p promotes myocardial remodeling in HF via the miR-339-3p-USP25-DDX58 signaling axis.
- This pathway represents a novel mechanism contributing to HF pathogenesis.
- miR-339-3p holds potential as a diagnostic biomarker and therapeutic target for heart failure.