Voigt, Niels

[["dc.bibliographiccitation.firstpage","1031"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Circulation Research"],["dc.bibliographiccitation.lastpage","1043"],["dc.bibliographiccitation.volume","109"],["dc.contributor.author","Makary, Samy"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Maguy, Ange"],["dc.contributor.author","Wakili, Reza"],["dc.contributor.author","Nishida, Kunihiro"],["dc.contributor.author","Harada, Masahide"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Nattel, Stanley"],["dc.date.accessioned","2022-03-01T11:43:50Z"],["dc.date.available","2022-03-01T11:43:50Z"],["dc.date.issued","2011"],["dc.description.abstract","Rationale: Atrial fibrillation (AF) causes atrial-tachycardia remodeling (ATR), with enhanced constitutive acetylcholine-regulated K + current (I KAChC ) contributing to action potential duration shortening and AF promotion. The underlying mechanisms are unknown. Objective: To evaluate the role of protein-kinase C (PKC) isoforms in ATR-induced I KAChC activation. Methods and Results: Cells from ATR-dogs (400-bpm atrial pacing for 1 week) were compared to control dog cells. In vitro tachypaced (TP; 3 Hz) canine atrial cardiomyocytes were compared to parallel 1-Hz paced cells. I KAChC single-channel activity was assessed in cell-attached and cell-free (inside-out) patches. Protein expression was assessed by immunoblot. In vitro TP activated I KAChC , mimicking effects of in vivo ATR. Discrepant effects of PKC activation and inhibition between control and ATR cells suggested isoform-selective effects and altered PKC isoform distribution. Conventional PKC isoforms (cPKC; including PKCα) inhibited, whereas novel isoforms (including PKCε) enhanced, acetylcholine-regulated K + current (I KACh ) in inside-out patches. TP and ATR downregulated PKCα (by 33% and 37%, respectively) and caused membrane translocation of PKCε, switching PKC predominance to the stimulatory novel isoform. TP increased [Ca 2+ ] i at 2 hours by 30%, with return to baseline at 24 hours. Buffering [Ca 2+ ] i during TP with the cell-permeable Ca 2+ chelator BAPTA-AM (1 μmol/L) or inhibiting the Ca 2+ -dependent protease calpain with PD150606 (20 μmol/L) prevented PKCα downregulation and TP enhancement of I KAChC . PKCε inhibition with a cell-permeable peptide inhibitor suppressed TP/ATR-induced I KAChC activation, whereas cPKC inhibition enhanced I KAChC activity in 1-Hz cells. Conclusions: PKC isoforms differentially modulate I KACh , with conventional Ca 2+ -dependent isoforms inhibiting and novel isoforms enhancing activity. ATR causes a rate-dependent PKC isoform switch, with Ca 2+ /calpain-dependent downregulation of inhibitory PKCα and membrane translocation of stimulatory PKCε, enhancing I KAChC . These findings provide novel insights into mechanisms underlying I KAChC dysregulation in AF."],["dc.description.abstract","Rationale: Atrial fibrillation (AF) causes atrial-tachycardia remodeling (ATR), with enhanced constitutive acetylcholine-regulated K + current (I KAChC ) contributing to action potential duration shortening and AF promotion. The underlying mechanisms are unknown. Objective: To evaluate the role of protein-kinase C (PKC) isoforms in ATR-induced I KAChC activation. Methods and Results: Cells from ATR-dogs (400-bpm atrial pacing for 1 week) were compared to control dog cells. In vitro tachypaced (TP; 3 Hz) canine atrial cardiomyocytes were compared to parallel 1-Hz paced cells. I KAChC single-channel activity was assessed in cell-attached and cell-free (inside-out) patches. Protein expression was assessed by immunoblot. In vitro TP activated I KAChC , mimicking effects of in vivo ATR. Discrepant effects of PKC activation and inhibition between control and ATR cells suggested isoform-selective effects and altered PKC isoform distribution. Conventional PKC isoforms (cPKC; including PKCα) inhibited, whereas novel isoforms (including PKCε) enhanced, acetylcholine-regulated K + current (I KACh ) in inside-out patches. TP and ATR downregulated PKCα (by 33% and 37%, respectively) and caused membrane translocation of PKCε, switching PKC predominance to the stimulatory novel isoform. TP increased [Ca 2+ ] i at 2 hours by 30%, with return to baseline at 24 hours. Buffering [Ca 2+ ] i during TP with the cell-permeable Ca 2+ chelator BAPTA-AM (1 μmol/L) or inhibiting the Ca 2+ -dependent protease calpain with PD150606 (20 μmol/L) prevented PKCα downregulation and TP enhancement of I KAChC . PKCε inhibition with a cell-permeable peptide inhibitor suppressed TP/ATR-induced I KAChC activation, whereas cPKC inhibition enhanced I KAChC activity in 1-Hz cells. Conclusions: PKC isoforms differentially modulate I KACh , with conventional Ca 2+ -dependent isoforms inhibiting and novel isoforms enhancing activity. ATR causes a rate-dependent PKC isoform switch, with Ca 2+ /calpain-dependent downregulation of inhibitory PKCα and membrane translocation of stimulatory PKCε, enhancing I KAChC . These findings provide novel insights into mechanisms underlying I KAChC dysregulation in AF."],["dc.identifier.doi","10.1161/CIRCRESAHA.111.253120"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102854"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4571"],["dc.relation.issn","0009-7330"],["dc.title","Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2576"],["dc.bibliographiccitation.issue","15"],["dc.bibliographiccitation.journal","British Journal of Pharmacology"],["dc.bibliographiccitation.lastpage","2590"],["dc.bibliographiccitation.volume","174"],["dc.contributor.author","Ji, Yuan"],["dc.contributor.author","Varkevisser, Rosanne"],["dc.contributor.author","Opacic, Dragan"],["dc.contributor.author","Bossu, Alexandre"],["dc.contributor.author","Kuiper, Marion"],["dc.contributor.author","Beekman, Jet D M"],["dc.contributor.author","Yang, Sihyung"],["dc.contributor.author","Khan, Azinwi Phina"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","van der Heyden, Marcel A G"],["dc.date.accessioned","2022-03-01T11:47:07Z"],["dc.date.available","2022-03-01T11:47:07Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1111/bph.13869"],["dc.identifier.issn","0007-1188"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103918"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.issn","0007-1188"],["dc.title","The inward rectifier current inhibitor PA-6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models"],["dc.title.alternative","I\r\n K1\r\n inhibitor PA-6 terminates atrial fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","C59"],["dc.bibliographiccitation.issue","16"],["dc.bibliographiccitation.journal","Journal of the American College of Cardiology"],["dc.bibliographiccitation.volume","64"],["dc.contributor.author","Li, Na"],["dc.contributor.author","Chiang, David Y."],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Martin, James F."],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Wehrens, Xander H.T."],["dc.date.accessioned","2022-03-01T11:45:10Z"],["dc.date.available","2022-03-01T11:45:10Z"],["dc.date.issued","2014"],["dc.identifier.doi","10.1016/j.jacc.2014.06.284"],["dc.identifier.pii","S0735109714031799"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103238"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.issn","0735-1097"],["dc.title","GW25-e5168 Impaired Post-Transcriptional Regulation of RyR2 by microRNA-106b-25 Cluster Promotes Atrial Fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","95"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","106"],["dc.bibliographiccitation.volume","94"],["dc.contributor.author","Hartmann, Nico H."],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Braun, Inga"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Schotola, Hanna"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Danner, Bernhard C."],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Belardinelli, Luiz"],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2017-09-07T11:44:54Z"],["dc.date.available","2017-09-07T11:44:54Z"],["dc.date.issued","2016"],["dc.description.abstract","Introduction: Pharmacological rhythm control of atrial fibrillation (AF) in patients with structural heart disease is limited. Ranolazine in combination with low dose dronedarone remarkably reduced AF-burden in the phase II HARMONY trial. We thus aimed to investigate the possible mechanisms underlying these results. Methods and results: Patch clamp experiments revealed that ranolazine (5 mu M), low-dose dronedarone (0.3 mu M), and the combination significantly prolonged action potential duration (APD(90)) in atrial myocytes from patients in sinus rhythm (prolongation by 23.5 +/- 0.1%, 31.7 +/- 0.1% and 25.6 +/- 0.1% respectively). Most importantly, in atrial myocytes from patients with AF ranolazine alone, but more the combination with dronedarone, also prolonged the typically abbreviated APD(90) (prolongation by 21.6 +/- 0.1% and 31.9 +/- 0.1% respectively). It was clearly observed that neither ranolazine, dronedarone nor the combination significantly changed the APD or contractility and twitch force in ventricular myocytes or trabeculae from patients with heart failure (HF). Interestingly ranolazine, and more so the combination, but not dronedarone alone, caused hyperpolarization of the resting membrane potential in cardiomyocytes from AF. As measured by confocal microscopy (Fluo-3), ranolazine, dronedarone and the combination significantly suppressed diastolic sarcoplasmic reticulum (SR) Ca2+ leak in myocytes from sinus rhythm (reduction by ranolazine: 89.0 +/- 30.7%, dronedarone: 75.6 +/- 27.4% and combination: 78.0 +/- 272%), in myocytes from AF (reduction by ranolazine: 67.6 +/- 33.7%, dronedarone: 86.5 +/- 31.7% and combination: 81.0 +/- 33.3%), as well as in myocytes from HF (reduction by ranolazine: 64.8 +/- 26.5% and dronedarone: 65.9 +/- 29.3%). Conclusions: Electrophysiological measurements during exposure to ranolazine alone or in combination with low-dose dronedarone showed APD prolongation, cellular hyperpolarization and reduced SR Ca2+ leak in human atrial myocytes. The combined inhibitory effects on various currents, in particular Na+ and K+ currents, may explain the anti-AF effects observed in the HARMONY trial. Therefore, the combination of ranolazine and dronedarone, but also ranolazine alone, may be promising new treatment options for AF, especially in patients with HF, and merit further clinical investigation. (C) 2016 Elsevier Ltd. All rights reserved."],["dc.identifier.doi","10.1016/j.yjmcc.2016.03.012"],["dc.identifier.gro","3141690"],["dc.identifier.isi","000376839000011"],["dc.identifier.pmid","27056421"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/8938"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/146"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation.eissn","1095-8584"],["dc.relation.issn","0022-2828"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG L. Maier (Experimentelle Kardiologie)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.title","The combined effects of ranolazine and dronedarone on human atrial and ventricular electrophysiology"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","187"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","198"],["dc.bibliographiccitation.volume","86"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Pearman, Charles M."],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Dibb, Katharine M."],["dc.date.accessioned","2022-03-01T11:45:25Z"],["dc.date.available","2022-03-01T11:45:25Z"],["dc.date.issued","2015"],["dc.identifier.doi","10.1016/j.yjmcc.2015.07.006"],["dc.identifier.pii","S0022282815300110"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103320"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.issn","0022-2828"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","Methods for isolating atrial cells from large mammals and humans"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Physiological Reports"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Trosclair, Krystle"],["dc.contributor.author","Si, Man"],["dc.contributor.author","Watts, Megan"],["dc.contributor.author","Gautier, Nicole M."],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Traylor, James"],["dc.contributor.author","Bitay, Miklós"],["dc.contributor.author","Baczko, Istvan"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Glasscock, Edward"],["dc.date.accessioned","2021-06-01T10:48:21Z"],["dc.date.available","2021-06-01T10:48:21Z"],["dc.date.issued","2021"],["dc.identifier.doi","10.14814/phy2.14702"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85904"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.relation.eissn","2051-817X"],["dc.relation.issn","2051-817X"],["dc.title","Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2059"],["dc.bibliographiccitation.issue","17"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","2070"],["dc.bibliographiccitation.volume","125"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Li, Na"],["dc.contributor.author","Wang, Qiongling"],["dc.contributor.author","Wang, Wei"],["dc.contributor.author","Trafford, Andrew W."],["dc.contributor.author","Abu-Taha, Issam"],["dc.contributor.author","Sun, Qiang"],["dc.contributor.author","Wieland, Thomas"],["dc.contributor.author","Ravens, Ursula"],["dc.contributor.author","Nattel, Stanley"],["dc.contributor.author","Dobrev, Dobromir"],["dc.date.accessioned","2022-03-01T11:43:52Z"],["dc.date.available","2022-03-01T11:43:52Z"],["dc.date.issued","2012"],["dc.description.abstract","Background— Delayed afterdepolarizations (DADs) carried by Na + -Ca 2+ -exchange current (I NCX ) in response to sarcoplasmic reticulum (SR) Ca 2+ leak can promote atrial fibrillation (AF). The mechanisms leading to delayed afterdepolarizations in AF patients have not been defined. Methods and Results— Protein levels (Western blot), membrane currents and action potentials (patch clamp), and [Ca 2+ ] i (Fluo-3) were measured in right atrial samples from 76 sinus rhythm (control) and 72 chronic AF (cAF) patients. Diastolic [Ca 2+ ] i and SR Ca 2+ content (integrated I NCX during caffeine-induced Ca 2+ transient) were unchanged, whereas diastolic SR Ca 2+ leak, estimated by blocking ryanodine receptors (RyR2) with tetracaine, was ≈50% higher in cAF versus control. Single-channel recordings from atrial RyR2 reconstituted into lipid bilayers revealed enhanced open probability in cAF samples, providing a molecular basis for increased SR Ca 2+ leak. Calmodulin expression (60%), Ca 2+ /calmodulin-dependent protein kinase-II (CaMKII) autophosphorylation at Thr287 (87%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 236%) and Ser2814 (CaMKII site, 77%) were increased in cAF. The selective CaMKII blocker KN-93 decreased SR Ca 2+ leak, the frequency of spontaneous Ca 2+ release events, and RyR2 open probability in cAF, whereas protein kinase A inhibition with H-89 was ineffective. Knock-in mice with constitutively phosphorylated RyR2 at Ser2814 showed a higher incidence of Ca 2+ sparks and increased susceptibility to pacing-induced AF compared with controls. The relationship between [Ca 2+ ] i and I NCX density revealed I NCX upregulation in cAF. Spontaneous Ca 2+ release events accompanied by inward I NCX currents and delayed afterdepolarizations/triggered activity occurred more often and the sensitivity of resting membrane voltage to elevated [Ca 2+ ] i (diastolic [Ca 2+ ] i –voltage coupling gain) was higher in cAF compared with control. Conclusions— Enhanced SR Ca 2+ leak through CaMKII-hyperphosphorylated RyR2, in combination with larger I NCX for a given SR Ca 2+ release and increased diastolic [Ca 2+ ] i -voltage coupling gain, causes AF-promoting atrial delayed afterdepolarizations/triggered activity in cAF patients."],["dc.description.abstract","Background— Delayed afterdepolarizations (DADs) carried by Na + -Ca 2+ -exchange current (I NCX ) in response to sarcoplasmic reticulum (SR) Ca 2+ leak can promote atrial fibrillation (AF). The mechanisms leading to delayed afterdepolarizations in AF patients have not been defined. Methods and Results— Protein levels (Western blot), membrane currents and action potentials (patch clamp), and [Ca 2+ ] i (Fluo-3) were measured in right atrial samples from 76 sinus rhythm (control) and 72 chronic AF (cAF) patients. Diastolic [Ca 2+ ] i and SR Ca 2+ content (integrated I NCX during caffeine-induced Ca 2+ transient) were unchanged, whereas diastolic SR Ca 2+ leak, estimated by blocking ryanodine receptors (RyR2) with tetracaine, was ≈50% higher in cAF versus control. Single-channel recordings from atrial RyR2 reconstituted into lipid bilayers revealed enhanced open probability in cAF samples, providing a molecular basis for increased SR Ca 2+ leak. Calmodulin expression (60%), Ca 2+ /calmodulin-dependent protein kinase-II (CaMKII) autophosphorylation at Thr287 (87%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 236%) and Ser2814 (CaMKII site, 77%) were increased in cAF. The selective CaMKII blocker KN-93 decreased SR Ca 2+ leak, the frequency of spontaneous Ca 2+ release events, and RyR2 open probability in cAF, whereas protein kinase A inhibition with H-89 was ineffective. Knock-in mice with constitutively phosphorylated RyR2 at Ser2814 showed a higher incidence of Ca 2+ sparks and increased susceptibility to pacing-induced AF compared with controls. The relationship between [Ca 2+ ] i and I NCX density revealed I NCX upregulation in cAF. Spontaneous Ca 2+ release events accompanied by inward I NCX currents and delayed afterdepolarizations/triggered activity occurred more often and the sensitivity of resting membrane voltage to elevated [Ca 2+ ] i (diastolic [Ca 2+ ] i –voltage coupling gain) was higher in cAF compared with control. Conclusions— Enhanced SR Ca 2+ leak through CaMKII-hyperphosphorylated RyR2, in combination with larger I NCX for a given SR Ca 2+ release and increased diastolic [Ca 2+ ] i -voltage coupling gain, causes AF-promoting atrial delayed afterdepolarizations/triggered activity in cAF patients."],["dc.identifier.doi","10.1161/CIRCULATIONAHA.111.067306"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102864"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4539"],["dc.relation.issn","0009-7322"],["dc.title","Enhanced Sarcoplasmic Reticulum Ca 2+ Leak and Increased Na + -Ca 2+ Exchanger Function Underlie Delayed Afterdepolarizations in Patients With Chronic Atrial Fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1214"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Circulation: Arrhythmia and Electrophysiology"],["dc.bibliographiccitation.lastpage","1222"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Chiang, David Y."],["dc.contributor.author","Kongchan, Natee"],["dc.contributor.author","Beavers, David L."],["dc.contributor.author","Alsina, Katherina M."],["dc.contributor.author","Voigt, N."],["dc.contributor.author","Neilson, Joel R."],["dc.contributor.author","Jakob, Heinz"],["dc.contributor.author","Martin, James F."],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Wehrens, Xander H.T."],["dc.contributor.author","Li, Na"],["dc.date.accessioned","2022-03-01T11:43:49Z"],["dc.date.available","2022-03-01T11:43:49Z"],["dc.date.issued","2014"],["dc.description.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."],["dc.description.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."],["dc.identifier.doi","10.1161/CIRCEP.114.001973"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102852"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1941-3084"],["dc.relation.issn","1941-3149"],["dc.title","Loss of MicroRNA-106b-25 Cluster Promotes Atrial Fibrillation by Enhancing Ryanodine Receptor Type-2 Expression and Calcium Release"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","77"],["dc.bibliographiccitation.journal","Journal of Visualized Experiments"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Zhou, Xiao-Bo"],["dc.contributor.author","Dobrev, Dobromir"],["dc.date.accessioned","2022-03-01T11:44:28Z"],["dc.date.available","2022-03-01T11:44:28Z"],["dc.date.issued","2013"],["dc.identifier.doi","10.3791/50235"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103034"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1940-087X"],["dc.title","Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca²⁺ Transients and Membrane Currents"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","392"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Heart Rhythm"],["dc.bibliographiccitation.lastpage","393"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Dobrev, Dobromir"],["dc.date.accessioned","2022-03-01T11:45:09Z"],["dc.date.available","2022-03-01T11:45:09Z"],["dc.date.issued","2013"],["dc.identifier.doi","10.1016/j.hrthm.2012.12.010"],["dc.identifier.pii","S1547527112014440"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103232"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.issn","1547-5271"],["dc.title","The biology of human pulmonary veins: Does it help us to better understand AF pathophysiology in patients?"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]