Loss of the miR-106b-25 cluster promotes atrial fibrillation susceptibility by increasing RyR2 protein expression by 42% and enhancing sarcoplasmic reticulum calcium leak.
Does loss of the miR-106b-25 cluster promote atrial fibrillation via enhanced RyR2-mediated sarcoplasmic reticulum Ca(2+)-leak?
The miR-106b-25 cluster regulates RyR2 expression, and its loss promotes atrial fibrillation via enhanced calcium leak, identifying it as a potential therapeutic target.
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.
Chiang et al. (Wed,) conducted a other in Atrial fibrillation. Loss of miR-106b-25 cluster vs. Wild-type littermates / patients in sinus rhythm was evaluated on RyR2 protein expression, sarcoplasmic reticulum Ca(2+)-leak, and AF susceptibility. Loss of the miR-106b-25 cluster promotes atrial fibrillation susceptibility by increasing RyR2 protein expression by 42% and enhancing sarcoplasmic reticulum calcium leak.