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Author Spotlight: Developing a Translational Model for Atrial Fibrillation Research Across Species
Published on: November 21, 2023
Small extracellular vesicles derived from patients with persistent atrial fibrillation exacerbate arrhythmogenesis
Dasom Mun1, Hyoeun Kim1, Ji-Young Kang1
1Department of Cardiology, Yonsei University College of Medicine, Seoul, Korea.
Abstract:
Small extracellular vesicles (sEVs) are nanometer-sized membranous vesicles that contribute to the pathogenesis of atrial fibrillation (AF). Here, we investigated the role of sEVs derived from patients with persistent AF in the pathophysiology of AF. First, we evaluated the pathological effects of sEVs derived from the peripheral blood of patients with persistent AF (AF-sEVs). AF-sEVs treatment reduced cell viability, caused abnormal Ca2+ handling, induced reactive oxygen species (ROS) production and led to increased CaMKII activation of non-paced and paced atrial cardiomyocytes. Next, we analyzed the miRNA profile of AF-sEVs to investigate which components of AF-sEVs promote arrhythmias, and we selected six miRNAs that correlated with CaMKII activation. qRT-PCR experiment identified that miR-30a-5p was significantly down-regulated in AF-sEVs, paced cardiomyocytes, and atrial tissues of patients with persistent AF. CaMKII was predicted by bioinformatics analysis as a miR-30a-5p target gene and validated by a dual luciferase reporter; hence, we evaluated the effects of miR-30a-5p on paced cardiomyocytes and validated miR-30a-5p as a pro-arrhythmic signature of AF-sEVs. Consequently, AF-sEVs-loaded with miR-30a-5p attenuated pacing-induced Ca2+-handling abnormalities, whereas AF-sEVs-loaded with anti-miR-30a-5p reversed the change in paced cardiomyocytes. Taken together, the regulation of CaMKII by miR-30a-5p revealed that miR-30a-5p is a major mediator for AF-sEVs-mediated AF pathogenesis. Accordingly, these findings suggest that sEVs derived from patients with persistent AF exacerbate arrhythmogenesis via miR-30a-5p.
Insights
Small extracellular vesicles (sEVs) from atrial fibrillation (AF) patients worsen AF by altering calcium handling via miR-30a-5p. This microRNA targets CaMKII, a key player in AF pathogenesis, highlighting sEVs as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cell Biology
Background:
- Small extracellular vesicles (sEVs) are implicated in atrial fibrillation (AF) pathogenesis.
- Understanding the specific role of AF-derived sEVs in AF pathophysiology is crucial.
Purpose of the Study:
- To investigate the pathological effects of sEVs from persistent AF patients on atrial cardiomyocytes.
- To identify key molecular components within AF-sEVs contributing to AF pathogenesis.
- To elucidate the role of miR-30a-5p in AF-sEV-mediated arrhythmogenesis.
Main Methods:
- Treatment of atrial cardiomyocytes with AF-sEVs.
- Analysis of miRNA profiles in AF-sEVs.
- qRT-PCR for miRNA and gene expression.
- Bioinformatics and dual luciferase reporter assays for miRNA-target interaction.
- Functional studies using engineered AF-sEVs with altered miR-30a-5p levels.
Main Results:
- AF-sEVs reduced cardiomyocyte viability, impaired calcium handling, increased ROS, and activated CaMKII.
- miR-30a-5p was significantly downregulated in AF-sEVs, cardiomyocytes, and AF atrial tissues.
- miR-30a-5p directly targets and regulates CaMKII activity.
- Restoring miR-30a-5p in AF-sEVs attenuated pacing-induced abnormalities, while inhibition exacerbated them.
Conclusions:
- AF-sEVs promote AF pathogenesis by disrupting cardiomyocyte function.
- miR-30a-5p acts as a critical mediator in AF-sEV-induced arrhythmogenesis by regulating CaMKII.
- Targeting miR-30a-5p within sEVs may offer a novel therapeutic strategy for AF.
