Voigt, Niels

[["dc.bibliographiccitation.firstpage","1276"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","1285"],["dc.bibliographiccitation.volume","129"],["dc.contributor.author","Li, Na"],["dc.contributor.author","Chiang, David Y."],["dc.contributor.author","Wang, Sufen"],["dc.contributor.author","Wang, Qiongling"],["dc.contributor.author","Sun, Liang"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Respress, Jonathan L."],["dc.contributor.author","Ather, Sameer"],["dc.contributor.author","Skapura, Darlene G."],["dc.contributor.author","Jordan, Valerie K."],["dc.contributor.author","Wehrens, Xander H.T."],["dc.date.accessioned","2022-03-01T11:43:53Z"],["dc.date.available","2022-03-01T11:43:53Z"],["dc.date.issued","2014"],["dc.description.abstract","Background— The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca 2+ leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca 2+ release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. Methods and Results— CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca 2+ release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca 2+ /calmodulin-dependent protein kinase II–mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca 2+ release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca 2+ -dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. Conclusions— RyR2-mediated SR Ca 2+ leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca 2+ release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate."],["dc.description.abstract","Background— The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca 2+ leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca 2+ release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. Methods and Results— CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca 2+ release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca 2+ /calmodulin-dependent protein kinase II–mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca 2+ release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca 2+ -dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. Conclusions— RyR2-mediated SR Ca 2+ leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca 2+ release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate."],["dc.identifier.doi","10.1161/CIRCULATIONAHA.113.006611"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102868"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4539"],["dc.relation.issn","0009-7322"],["dc.title","Ryanodine Receptor–Mediated Calcium Leak Drives Progressive Development of an Atrial Fibrillation Substrate in a Transgenic Mouse Model"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["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","1474"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Circulation Research"],["dc.bibliographiccitation.lastpage","1483"],["dc.bibliographiccitation.volume","110"],["dc.contributor.author","Respress, Jonathan L."],["dc.contributor.author","van Oort, Ralph J."],["dc.contributor.author","Li, Na"],["dc.contributor.author","Rolim, Natale"],["dc.contributor.author","Dixit, Sayali S."],["dc.contributor.author","deAlmeida, Angela"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Lawrence, William S."],["dc.contributor.author","Skapura, Darlene G."],["dc.contributor.author","Skårdal, Kristine"],["dc.contributor.author","Wehrens, Xander H.T."],["dc.date.accessioned","2022-03-01T11:43:51Z"],["dc.date.available","2022-03-01T11:43:51Z"],["dc.date.issued","2012"],["dc.identifier.doi","10.1161/CIRCRESAHA.112.268094"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102858"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4571"],["dc.relation.issn","0009-7330"],["dc.title","Role of RyR2 Phosphorylation at S2814 During Heart Failure Progression"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["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.firstpage","190"],["dc.bibliographiccitation.journal","International Journal of Cardiology"],["dc.bibliographiccitation.lastpage","197"],["dc.bibliographiccitation.volume","184"],["dc.contributor.author","Chiang, David Y."],["dc.contributor.author","Zhang, Min"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Alsina, Katherina M."],["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","2022-03-01T11:45:10Z"],["dc.date.available","2022-03-01T11:45:10Z"],["dc.date.issued","2015"],["dc.identifier.doi","10.1016/j.ijcard.2015.01.075"],["dc.identifier.pii","S0167527315001023"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103234"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.issn","0167-5273"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","Identification of microRNA–mRNA dysregulations in paroxysmal atrial fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1212"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","1222"],["dc.bibliographiccitation.volume","124"],["dc.contributor.author","Cunha, Shane R."],["dc.contributor.author","Hund, Thomas J."],["dc.contributor.author","Hashemi, Seyed"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Li, Na"],["dc.contributor.author","Wright, Patrick"],["dc.contributor.author","Koval, Olha"],["dc.contributor.author","Li, Jingdong"],["dc.contributor.author","Gudmundsson, Hjalti"],["dc.contributor.author","Gumina, Richard J."],["dc.contributor.author","Mohler, Peter J."],["dc.date.accessioned","2022-03-01T11:43:52Z"],["dc.date.available","2022-03-01T11:43:52Z"],["dc.date.issued","2011"],["dc.description.abstract","Background— Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting >2 million patients in the United States alone. Despite decades of research, surprisingly little is known regarding the molecular pathways underlying the pathogenesis of AF. ANK2 encodes ankyrin-B, a multifunctional adapter molecule implicated in membrane targeting of ion channels, transporters, and signaling molecules in excitable cells. Methods and Results— In the present study, we report early-onset AF in patients harboring loss-of-function mutations in ANK2 . In mice, we show that ankyrin-B deficiency results in atrial electrophysiological dysfunction and increased susceptibility to AF. Moreover, ankyrin-B +/− atrial myocytes display shortened action potentials, consistent with human AF. Ankyrin-B is expressed in atrial myocytes, and we demonstrate its requirement for the membrane targeting and function of a subgroup of voltage-gated Ca 2+ channels (Ca v 1.3) responsible for low voltage-activated L-type Ca 2+ current. Ankyrin-B is associated directly with Ca v 1.3, and this interaction is regulated by a short, highly conserved motif specific to Ca v 1.3. Moreover, loss of ankyrin-B in atrial myocytes results in decreased Ca v 1.3 expression, membrane localization, and function sufficient to produce shortened atrial action potentials and arrhythmias. Finally, we demonstrate reduced ankyrin-B expression in atrial samples of patients with documented AF, further supporting an association between ankyrin-B and AF. Conclusions— These findings support that reduced ankyrin-B expression or mutations in ANK2 are associated with AF. Additionally, our data demonstrate a novel pathway for ankyrin-B–dependent regulation of Ca v 1.3 channel membrane targeting and regulation in atrial myocytes."],["dc.description.abstract","Background— Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting >2 million patients in the United States alone. Despite decades of research, surprisingly little is known regarding the molecular pathways underlying the pathogenesis of AF. ANK2 encodes ankyrin-B, a multifunctional adapter molecule implicated in membrane targeting of ion channels, transporters, and signaling molecules in excitable cells. Methods and Results— In the present study, we report early-onset AF in patients harboring loss-of-function mutations in ANK2 . In mice, we show that ankyrin-B deficiency results in atrial electrophysiological dysfunction and increased susceptibility to AF. Moreover, ankyrin-B +/− atrial myocytes display shortened action potentials, consistent with human AF. Ankyrin-B is expressed in atrial myocytes, and we demonstrate its requirement for the membrane targeting and function of a subgroup of voltage-gated Ca 2+ channels (Ca v 1.3) responsible for low voltage-activated L-type Ca 2+ current. Ankyrin-B is associated directly with Ca v 1.3, and this interaction is regulated by a short, highly conserved motif specific to Ca v 1.3. Moreover, loss of ankyrin-B in atrial myocytes results in decreased Ca v 1.3 expression, membrane localization, and function sufficient to produce shortened atrial action potentials and arrhythmias. Finally, we demonstrate reduced ankyrin-B expression in atrial samples of patients with documented AF, further supporting an association between ankyrin-B and AF. Conclusions— These findings support that reduced ankyrin-B expression or mutations in ANK2 are associated with AF. Additionally, our data demonstrate a novel pathway for ankyrin-B–dependent regulation of Ca v 1.3 channel membrane targeting and regulation in atrial myocytes."],["dc.identifier.doi","10.1161/CIRCULATIONAHA.111.023986"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102863"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4539"],["dc.relation.issn","0009-7322"],["dc.title","Defects in Ankyrin-Based Membrane Protein Targeting Pathways Underlie Atrial Fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","178"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cardiovascular Research"],["dc.bibliographiccitation.lastpage","187"],["dc.bibliographiccitation.volume","103"],["dc.contributor.author","Chiang, David Y."],["dc.contributor.author","Li, Na"],["dc.contributor.author","Wang, Qiongling"],["dc.contributor.author","Alsina, Katherina M."],["dc.contributor.author","Quick, Ann P."],["dc.contributor.author","Reynolds, Julia O."],["dc.contributor.author","Wang, Guoliang"],["dc.contributor.author","Skapura, Darlene"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Wehrens, Xander H.T."],["dc.date.accessioned","2022-03-01T11:46:42Z"],["dc.date.available","2022-03-01T11:46:42Z"],["dc.date.issued","2014"],["dc.identifier.doi","10.1093/cvr/cvu123"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103769"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1755-3245"],["dc.relation.issn","0008-6363"],["dc.title","Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1748"],["dc.bibliographiccitation.issue","16"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","1757"],["dc.bibliographiccitation.volume","128"],["dc.contributor.author","Purohit, Anil"],["dc.contributor.author","Rokita, Adam G."],["dc.contributor.author","Guan, Xiaoqun"],["dc.contributor.author","Chen, Biyi"],["dc.contributor.author","Koval, Olha M."],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Neef, Stefan"],["dc.contributor.author","Sowa, Thomas"],["dc.contributor.author","Gao, Zhan"],["dc.contributor.author","Luczak, Elizabeth D."],["dc.contributor.author","Stefansdottir, Hrafnhildur"],["dc.contributor.author","Behunin, Andrew C."],["dc.contributor.author","Li, Na"],["dc.contributor.author","El-Accaoui, Ramzi N."],["dc.contributor.author","Yang, Baoli"],["dc.contributor.author","Swaminathan, Paari Dominic"],["dc.contributor.author","Weiss, Robert M."],["dc.contributor.author","Wehrens, Xander H.T."],["dc.contributor.author","Song, Long-Sheng"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Anderson, Mark E."],["dc.date.accessioned","2018-11-07T09:18:37Z"],["dc.date.available","2018-11-07T09:18:37Z"],["dc.date.issued","2013"],["dc.description.abstract","Background Atrial fibrillation (AF) is a growing public health problem without adequate therapies. Angiotensin II and reactive oxygen species are validated risk factors for AF in patients, but the molecular pathways connecting reactive oxygen species and AF are unknown. The Ca2+/calmodulin-dependent protein kinase II (CaMKII) has recently emerged as a reactive oxygen species-activated proarrhythmic signal, so we hypothesized that oxidized CaMKII could contribute to AF. Methods and Results We found that oxidized CaMKII was increased in atria from AF patients compared with patients in sinus rhythm and from mice infused with angiotensin II compared with mice infused with saline. Angiotensin II-treated mice had increased susceptibility to AF compared with saline-treated wild-type mice, establishing angiotensin II as a risk factor for AF in mice. Knock-in mice lacking critical oxidation sites in CaMKII (MM-VV) and mice with myocardium-restricted transgenic overexpression of methionine sulfoxide reductase A, an enzyme that reduces oxidized CaMKII, were resistant to AF induction after angiotensin II infusion. Conclusions Our studies suggest that CaMKII is a molecular signal that couples increased reactive oxygen species with AF and that therapeutic strategies to decrease oxidized CaMKII may prevent or reduce AF."],["dc.identifier.doi","10.1161/CIRCULATIONAHA.113.003313"],["dc.identifier.isi","000325686800016"],["dc.identifier.pmid","24030498"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/28445"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/48"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz"],["dc.relation.issn","1524-4539"],["dc.relation.issn","0009-7322"],["dc.relation.workinggroup","RG L. Maier (Experimentelle Kardiologie)"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.title","Oxidized Ca2+/Calmodulin-Dependent Protein Kinase II Triggers Atrial Fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","145"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","156"],["dc.bibliographiccitation.volume","129"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Heijman, Jordi"],["dc.contributor.author","Wang, Qiongling"],["dc.contributor.author","Chiang, David Y."],["dc.contributor.author","Li, Na"],["dc.contributor.author","Karck, Matthias"],["dc.contributor.author","Wehrens, Xander H.T."],["dc.contributor.author","Nattel, Stanley"],["dc.contributor.author","Dobrev, Dobromir"],["dc.date.accessioned","2022-03-01T11:43:54Z"],["dc.date.available","2022-03-01T11:43:54Z"],["dc.date.issued","2014"],["dc.description.abstract","Background— Electrical, structural, and Ca 2+ -handling remodeling contribute to the perpetuation/progression of atrial fibrillation (AF). Recent evidence has suggested a role for spontaneous sarcoplasmic reticulum Ca 2+ -release events in long-standing persistent AF, but the occurrence and mechanisms of sarcoplasmic reticulum Ca 2+ -release events in paroxysmal AF (pAF) are unknown. Method and Results— Right-atrial appendages from control sinus rhythm patients or patients with pAF (last episode a median of 10–20 days preoperatively) were analyzed with simultaneous measurements of [Ca 2+ ] i (fluo-3-acetoxymethyl ester) and membrane currents/action potentials (patch-clamp) in isolated atrial cardiomyocytes, and Western blot. Action potential duration, L-type Ca 2+ current, and Na + /Ca 2+ -exchange current were unaltered in pAF, indicating the absence of AF-induced electrical remodeling. In contrast, there were increases in SR Ca 2+ leak and incidence of delayed after-depolarizations in pAF. Ca 2+ -transient amplitude and sarcoplasmic reticulum Ca 2+ load (caffeine-induced Ca 2+ -transient amplitude, integrated Na + /Ca 2+ -exchange current) were larger in pAF. Ca 2+ -transient decay was faster in pAF, but the decay of caffeine-induced Ca 2+ transients was unaltered, suggesting increased SERCA2a function. In agreement, phosphorylation (inactivation) of the SERCA2a-inhibitor protein phospholamban was increased in pAF. Ryanodine receptor fractional phosphorylation was unaltered in pAF, whereas ryanodine receptor expression and single-channel open probability were increased. A novel computational model of the human atrial cardiomyocyte indicated that both ryanodine receptor dysregulation and enhanced SERCA2a activity promote increased sarcoplasmic reticulum Ca 2+ leak and sarcoplasmic reticulum Ca 2+ -release events, causing delayed after-depolarizations/triggered activity in pAF. Conclusions— Increased diastolic sarcoplasmic reticulum Ca 2+ leak and related delayed after-depolarizations/triggered activity promote cellular arrhythmogenesis in pAF patients. Biochemical, functional, and modeling studies point to a combination of increased sarcoplasmic reticulum Ca 2+ load related to phospholamban hyperphosphorylation and ryanodine receptor dysregulation as underlying mechanisms."],["dc.description.abstract","Background— Electrical, structural, and Ca 2+ -handling remodeling contribute to the perpetuation/progression of atrial fibrillation (AF). Recent evidence has suggested a role for spontaneous sarcoplasmic reticulum Ca 2+ -release events in long-standing persistent AF, but the occurrence and mechanisms of sarcoplasmic reticulum Ca 2+ -release events in paroxysmal AF (pAF) are unknown. Method and Results— Right-atrial appendages from control sinus rhythm patients or patients with pAF (last episode a median of 10–20 days preoperatively) were analyzed with simultaneous measurements of [Ca 2+ ] i (fluo-3-acetoxymethyl ester) and membrane currents/action potentials (patch-clamp) in isolated atrial cardiomyocytes, and Western blot. Action potential duration, L-type Ca 2+ current, and Na + /Ca 2+ -exchange current were unaltered in pAF, indicating the absence of AF-induced electrical remodeling. In contrast, there were increases in SR Ca 2+ leak and incidence of delayed after-depolarizations in pAF. Ca 2+ -transient amplitude and sarcoplasmic reticulum Ca 2+ load (caffeine-induced Ca 2+ -transient amplitude, integrated Na + /Ca 2+ -exchange current) were larger in pAF. Ca 2+ -transient decay was faster in pAF, but the decay of caffeine-induced Ca 2+ transients was unaltered, suggesting increased SERCA2a function. In agreement, phosphorylation (inactivation) of the SERCA2a-inhibitor protein phospholamban was increased in pAF. Ryanodine receptor fractional phosphorylation was unaltered in pAF, whereas ryanodine receptor expression and single-channel open probability were increased. A novel computational model of the human atrial cardiomyocyte indicated that both ryanodine receptor dysregulation and enhanced SERCA2a activity promote increased sarcoplasmic reticulum Ca 2+ leak and sarcoplasmic reticulum Ca 2+ -release events, causing delayed after-depolarizations/triggered activity in pAF. Conclusions— Increased diastolic sarcoplasmic reticulum Ca 2+ leak and related delayed after-depolarizations/triggered activity promote cellular arrhythmogenesis in pAF patients. Biochemical, functional, and modeling studies point to a combination of increased sarcoplasmic reticulum Ca 2+ load related to phospholamban hyperphosphorylation and ryanodine receptor dysregulation as underlying mechanisms."],["dc.identifier.doi","10.1161/CIRCULATIONAHA.113.006641"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102869"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4539"],["dc.relation.issn","0009-7322"],["dc.title","Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]