Loss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release

Circ Arrhythm Electrophysiol. 2014 Dec;7(6):1214-22. doi: 10.1161/CIRCEP.114.001973. Epub 2014 Nov 11.


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.

Keywords: atrial fibrillation; microRNA; ryanodine receptor calcium release channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Action Potentials
  • Animals
  • Atrial Fibrillation / genetics
  • Atrial Fibrillation / metabolism*
  • Atrial Fibrillation / physiopathology
  • Calcium / metabolism*
  • Calcium Signaling
  • Case-Control Studies
  • Disease Models, Animal
  • Down-Regulation
  • Gene Knockdown Techniques
  • Humans
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Myocardium / metabolism*
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcoplasmic Reticulum / metabolism*
  • Time Factors
  • Transcription, Genetic
  • Up-Regulation


  • 3' Untranslated Regions
  • MIRN106 microRNA, human
  • MicroRNAs
  • Mirn106 microRNA, mouse
  • Ryanodine Receptor Calcium Release Channel
  • ryanodine receptor 2. mouse
  • Calcium