Loss of MicroRNA-106b-25 Cluster Promotes Atrial Fibrillation by Enhancing Ryanodine Receptor Type-2 Expression and Calcium Release
2014 | journal article
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Loss of MicroRNA-106b-25 Cluster Promotes Atrial Fibrillation by Enhancing Ryanodine Receptor Type-2 Expression and Calcium Release
Chiang, D. Y.; Kongchan, N.; Beavers, D. L.; Alsina, K. M.; Voigt, N. ; Neilson, J. R. & Jakob, H. et al. (2014)
Circulation: Arrhythmia and Electrophysiology, 7(6) pp. 1214-1222. DOI: https://doi.org/10.1161/CIRCEP.114.001973
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Details
- Authors
- Chiang, David Y.; Kongchan, Natee; Beavers, David L.; Alsina, Katherina M.; Voigt, N. ; Neilson, Joel R.; Jakob, Heinz; Martin, James F.; Dobrev, Dobromir; Wehrens, Xander H.T.; Li, Na
- Abstract
- Background— Enhanced sarcoplasmic reticulum Ca 2+ -leak via ryanodine receptor type-2 (RyR2) contributes to the pathogenesis of atrial fibrillation (AF). Recent studies have shown that the level of RyR2 protein is elevated in atria of patients with paroxysmal AF, suggesting that microRNA-mediated post-transcriptional regulation of RyR2 might be an underlying mechanism. Bioinformatic analysis suggests that miR-106b and miR-93, members of the miR-106b-25 cluster, could bind to RyR2-3′-untranslated region and suppress its translation. Thus, we tested the hypothesis that loss of the miR-106b-25 cluster promotes AF via enhanced RyR2-mediated sarcoplasmic reticulum Ca 2+ -leak. Methods and Results— Quantitative real-time polymerase chain reaction showed that the levels of mature miR-106b, miR-93, and miR-25 were lower in atria of patients with paroxysmal AF when compared with patients in sinus rhythm. In vitro assay showed that miR-93 reduced RyR2-3′-untranslated region luciferase activity. Total RyR2 protein in atrial tissue of miR-106b-25 −/− mice was increased by 42% when compared with wild-type littermates but still maintained a normal subcellular distribution. Ca 2+ -spark frequency and total sarcoplasmic reticulum Ca 2+ -leak were increased in atrial myocytes of miR-106b-25 −/− mice. Telemetry ECG recordings revealed that miR-106b-25 −/− mice exhibited more frequent atrial ectopy and were also more susceptible to pacing-induced AF than wild-type littermates. Increased sarcoplasmic reticulum Ca 2+ -release and AF susceptibility in miR-106b-25 −/− mice were abolished by the RyR2 blocker K201. Conclusions— These results suggest that miR-106b-25 cluster–mediated post-transcriptional regulation of RyR2 is a potential molecular mechanism involved in paroxysmal AF pathogenesis. As such, the miR-106b-25 cluster could be a novel gene-therapy target in AF associated with enhanced RyR2 expression.
Background— Enhanced sarcoplasmic reticulum Ca 2+ -leak via ryanodine receptor type-2 (RyR2) contributes to the pathogenesis of atrial fibrillation (AF). Recent studies have shown that the level of RyR2 protein is elevated in atria of patients with paroxysmal AF, suggesting that microRNA-mediated post-transcriptional regulation of RyR2 might be an underlying mechanism. Bioinformatic analysis suggests that miR-106b and miR-93, members of the miR-106b-25 cluster, could bind to RyR2-3′-untranslated region and suppress its translation. Thus, we tested the hypothesis that loss of the miR-106b-25 cluster promotes AF via enhanced RyR2-mediated sarcoplasmic reticulum Ca 2+ -leak. Methods and Results— Quantitative real-time polymerase chain reaction showed that the levels of mature miR-106b, miR-93, and miR-25 were lower in atria of patients with paroxysmal AF when compared with patients in sinus rhythm. In vitro assay showed that miR-93 reduced RyR2-3′-untranslated region luciferase activity. Total RyR2 protein in atrial tissue of miR-106b-25 −/− mice was increased by 42% when compared with wild-type littermates but still maintained a normal subcellular distribution. Ca 2+ -spark frequency and total sarcoplasmic reticulum Ca 2+ -leak were increased in atrial myocytes of miR-106b-25 −/− mice. Telemetry ECG recordings revealed that miR-106b-25 −/− mice exhibited more frequent atrial ectopy and were also more susceptible to pacing-induced AF than wild-type littermates. Increased sarcoplasmic reticulum Ca 2+ -release and AF susceptibility in miR-106b-25 −/− mice were abolished by the RyR2 blocker K201. Conclusions— These results suggest that miR-106b-25 cluster–mediated post-transcriptional regulation of RyR2 is a potential molecular mechanism involved in paroxysmal AF pathogenesis. As such, the miR-106b-25 cluster could be a novel gene-therapy target in AF associated with enhanced RyR2 expression. - Issue Date
- 2014
- Journal
- Circulation: Arrhythmia and Electrophysiology
- ISSN
- 1941-3149
- eISSN
- 1941-3084
- Language
- English