David Y Chiang1, Natee Kongchan1, David L Beavers1, Katherina M Alsina1, Niels Voigt1, Joel R Neilson1, Heinz Jakob1, James F Martin1, Dobromir Dobrev1, Xander H T Wehrens1, Na Li2. 1. From the Cardiovascular Research Institute (D.Y.C., D.L.B., K.M.A., J.F.M., X.H.T.W., N.L.), Department of Molecular Physiology and Biophysics (D.Y.C., N.K., D.L.B., K.M.A., J.R.N., J.F.M., X.H.T.W., N.L.) Interdepartmental Program in Translational Biology and Molecular Medicine (D.Y.C., D.L.B.), Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; Texas Heart Institute, Houston (J.F.M.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.); and Department of Thoracic and Cardiovascular Surgery, University Hospital, Essen, Germany (H.J.). 2. From the Cardiovascular Research Institute (D.Y.C., D.L.B., K.M.A., J.F.M., X.H.T.W., N.L.), Department of Molecular Physiology and Biophysics (D.Y.C., N.K., D.L.B., K.M.A., J.R.N., J.F.M., X.H.T.W., N.L.) Interdepartmental Program in Translational Biology and Molecular Medicine (D.Y.C., D.L.B.), Department of Medicine (Cardiology) (X.H.T.W.), Baylor College of Medicine, Houston, TX; Texas Heart Institute, Houston (J.F.M.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.); and Department of Thoracic and Cardiovascular Surgery, University Hospital, Essen, Germany (H.J.). nal@bcm.edu.
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.
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