Voigt, Niels

[["dc.bibliographiccitation.firstpage","530"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Circulation: Arrhythmia and Electrophysiology"],["dc.bibliographiccitation.lastpage","541"],["dc.bibliographiccitation.volume","3"],["dc.contributor.author","Wakili, Reza"],["dc.contributor.author","Yeh, Yung-Hsin"],["dc.contributor.author","Yan Qi, Xiao"],["dc.contributor.author","Greiser, Maura"],["dc.contributor.author","Chartier, Denis"],["dc.contributor.author","Nishida, Kunihiro"],["dc.contributor.author","Maguy, Ange"],["dc.contributor.author","Villeneuve, Louis-Robert"],["dc.contributor.author","Boknik, Peter"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Nattel, Stanley"],["dc.date.accessioned","2022-03-01T11:43:49Z"],["dc.date.available","2022-03-01T11:43:49Z"],["dc.date.issued","2010"],["dc.identifier.doi","10.1161/CIRCEP.109.933036"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102850"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1941-3084"],["dc.relation.issn","1941-3149"],["dc.title","Multiple Potential Molecular Contributors to Atrial Hypocontractility Caused by Atrial Tachycardia Remodeling in Dogs"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["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","2051"],["dc.bibliographiccitation.issue","17"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","2064"],["dc.bibliographiccitation.volume","126"],["dc.contributor.author","Harada, Masahide"],["dc.contributor.author","Luo, Xiaobin"],["dc.contributor.author","Qi, Xiao Yan"],["dc.contributor.author","Tadevosyan, Artavazd"],["dc.contributor.author","Maguy, Ange"],["dc.contributor.author","Ordog, Balazs"],["dc.contributor.author","Ledoux, Jonathan"],["dc.contributor.author","Kato, Takeshi"],["dc.contributor.author","Naud, Patrice"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Nattel, Stanley"],["dc.date.accessioned","2022-03-01T11:43:53Z"],["dc.date.available","2022-03-01T11:43:53Z"],["dc.date.issued","2012"],["dc.description.abstract","Background— Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)–promoting remodeling. Here, we investigated fibroblast regulation by Ca 2+ -permeable transient receptor potential canonical-3 (TRPC3) channels. Methods and Results— Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents ( I NSC ) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II–induced Ca 2+ influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca 2+ removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA [shRNA]) decreased canine atrial fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5′ promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression. Conclusions— TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca 2+ influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target."],["dc.description.abstract","Background— Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)–promoting remodeling. Here, we investigated fibroblast regulation by Ca 2+ -permeable transient receptor potential canonical-3 (TRPC3) channels. Methods and Results— Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents ( I NSC ) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II–induced Ca 2+ influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca 2+ removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA [shRNA]) decreased canine atrial fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5′ promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression. Conclusions— TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca 2+ influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target."],["dc.identifier.doi","10.1161/CIRCULATIONAHA.112.121830"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102867"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4539"],["dc.relation.issn","0009-7322"],["dc.title","Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial Fibrillation"],["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","472"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Circulation: Arrhythmia and Electrophysiology"],["dc.bibliographiccitation.lastpage","480"],["dc.bibliographiccitation.volume","3"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Trausch, Anne"],["dc.contributor.author","Knaut, Michael"],["dc.contributor.author","Matschke, Klaus"],["dc.contributor.author","Varró, András"],["dc.contributor.author","Van Wagoner, David R."],["dc.contributor.author","Nattel, Stanley"],["dc.contributor.author","Ravens, Ursula"],["dc.contributor.author","Dobrev, Dobromir"],["dc.date.accessioned","2022-03-01T11:43:49Z"],["dc.date.available","2022-03-01T11:43:49Z"],["dc.date.issued","2010"],["dc.identifier.doi","10.1161/CIRCEP.110.954636"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102851"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1941-3084"],["dc.relation.issn","1941-3149"],["dc.title","Left-to-Right Atrial Inward Rectifier Potassium Current Gradients in Patients With Paroxysmal Versus Chronic Atrial Fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1175"],["dc.bibliographiccitation.lastpage","1191"],["dc.bibliographiccitation.seriesnr","740"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Nattel, Stanley"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.editor","Islam, Md. Shahidul"],["dc.date.accessioned","2022-03-01T11:47:07Z"],["dc.date.available","2022-03-01T11:47:07Z"],["dc.date.issued","2012"],["dc.identifier.doi","10.1007/978-94-007-2888-2_53"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103915"],["dc.notes.intern","DOI-Import GROB-531"],["dc.publisher","Springer Netherlands"],["dc.publisher.place","Dordrecht"],["dc.relation.crisseries","Advances in Experimental Medicine and Biology"],["dc.relation.eisbn","978-94-007-2888-2"],["dc.relation.isbn","978-94-007-2887-5"],["dc.relation.ispartof","Calcium Signaling"],["dc.title","Proarrhythmic Atrial Calcium Cycling in the Diseased Heart"],["dc.type","book_chapter"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2192"],["dc.bibliographiccitation.issue","20"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","U67"],["dc.bibliographiccitation.volume","123"],["dc.contributor.author","Tsuji, Yukiomi"],["dc.contributor.author","Hojo, Mayumi"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Inden, Yasuya"],["dc.contributor.author","Murohara, Toyoaki"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Nattel, Stanley"],["dc.contributor.author","Kodama, Itsuo"],["dc.contributor.author","Kamiya, Kaichiro"],["dc.date.accessioned","2018-11-07T08:56:04Z"],["dc.date.available","2018-11-07T08:56:04Z"],["dc.date.issued","2011"],["dc.description.abstract","Background-Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, typically occurs in implantable cardioverter-defibrillator patients and adversely affects prognosis. However, the underlying molecular basis is poorly understood. In the present study, we report a new experimental model featuring repetitive episodes of implantable cardioverter-defibrillator firing for recurrent ventricular fibrillation (VF), in which we assessed involvement of Ca2+-related protein alterations in ES. Methods and Results-We studied 37 rabbits with complete atrioventricular block for approximate to 80 days, all with implantable cardioverter-defibrillator implantation. All rabbits showed long-QT and VF episodes. Fifty-three percent of rabbits developed ES (>= 3 VF episodes per 24-hour period; 103 +/- 23 VF episodes per rabbit). Expression/phosphorylation of Ca2+-handling proteins was assessed in left ventricular tissues from rabbits with the following: ES; VF episodes but not ES (non-ES); and controls. Left ventricular end-diastolic diameter increased comparably in ES and non-ES rabbits, but contractile dysfunction was significantly greater in ES than in non-ES rabbits. ES rabbits showed striking hyperphosphorylation of Ca2+/calmodulin-dependent protein kinase II, prominent phospholamban dephosphorylation, and increased protein phosphatase 1 and 2A expression versus control and non-ES rabbits. Ryanodine receptors were similarly hyperphosphorylated at Ser2815 in ES and non-ES rabbits, but ryanodine receptor Ser2809 and L-type Ca2+-channel alpha-subunit hyperphosphorylation were significantly greater in ES versus non-ES rabbits. To examine direct effects of repeated VF/defibrillation, VF was induced 10 times in control rabbits. Repeated VF tissues showed autophosphorylated Ca2+/calmodulin-dependent protein kinase II upregulation and phospholamban dephosphorylation like those of ES rabbit hearts. Continuous infusion of a calmodulin antagonist (W-7) to ES rabbits reduced Ca2+/calmodulin-dependent protein kinase II hyperphosphorylation, suppressed ventricular tachycardia/fibrillation, and rescued left ventricular dysfunction. Conclusions-ES causes Ca2+/calmodulin-dependent protein kinase II activation and phospholamban dephosphorylation, which can explain the vicious cycle of arrhythmia promotion and mechanical dysfunction that characterizes ES. (Circulation. 2011; 123: 2192-2203.)"],["dc.identifier.doi","10.1161/CIRCULATIONAHA.110.016683"],["dc.identifier.isi","000290852200013"],["dc.identifier.pmid","21555709"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/23054"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Lippincott Williams & Wilkins"],["dc.relation.issn","0009-7322"],["dc.title","Ca2+-Related Signaling and Protein Phosphorylation Abnormalities Play Central Roles in a New Experimental Model of Electrical Storm"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1466"],["dc.bibliographiccitation.issue","14"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","1475"],["dc.bibliographiccitation.volume","127"],["dc.contributor.author","Dawson, Kristin"],["dc.contributor.author","Wakili, Reza"],["dc.contributor.author","Ördög, Balázs"],["dc.contributor.author","Clauss, Sebastian"],["dc.contributor.author","Chen, Yu"],["dc.contributor.author","Iwasaki, Yuki"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Qi, Xiao Yan"],["dc.contributor.author","Sinner, Moritz F."],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Nattel, Stanley"],["dc.date.accessioned","2022-03-01T11:43:53Z"],["dc.date.available","2022-03-01T11:43:53Z"],["dc.date.issued","2013"],["dc.description.abstract","Background— Congestive heart failure (CHF) causes atrial fibrotic remodeling, a substrate for atrial fibrillation (AF) maintenance. MicroRNA29 (miR29) targets extracellular matrix proteins. In the present study, we examined miR29b changes in patients with AF and/or CHF and in a CHF-related AF animal model and assessed its potential role in controlling atrial fibrous tissue production. Methods and Results— Control dogs were compared with dogs subjected to ventricular tachypacing for 24 hours, 1 week, or 2 weeks to induce CHF. Atrial miR29b expression decreased within 24 hours in both whole atrial tissue and atrial fibroblasts (−87% and −92% versus control, respectively; p <0.001 for both) and remained decreased throughout the time course. Expression of miR29b extracellular matrix target genes collagen-1A1 (COL1A1), collagen-3A1 (COL3A1), and fibrillin increased significantly in CHF fibroblasts. Lentivirus-mediated miR29b knockdown in canine atrial fibroblasts (−68%; p <0.01) enhanced COL1A1, COL3A1, and fibrillin mRNA expression by 28% ( p <0.01), 19% ( p <0.05), and 20% ( p <0.05), respectively, versus empty virus–infected fibroblasts and increased COL1A1 protein expression by 90% ( p <0.05). In contrast, 3-fold overexpression of miR29b decreased COL1A1, COL3A1, and fibrillin mRNA by 65%, 62%, and 61% (all p <0.001), respectively, versus scrambled control and decreased COL1A1 protein by 60% ( p <0.05). MiR29b plasma levels were decreased in patients with CHF or AF (by 53% and 54%, respectively; both p <0.001) and were further decreased in patients with both AF and CHF (by 84%; p <0.001). MiR29b expression was also reduced in the atria of chronic AF patients (by 54% versus sinus rhythm; p <0.05). Adenoassociated viral–mediated knockdown of miR29b in mice significantly increased atrial COL1A1 mRNA expression and cardiac tissue collagen content. Conclusions— MiR29 likely plays a role in atrial fibrotic remodeling and may have value as a biomarker and/or therapeutic target."],["dc.description.abstract","Background— Congestive heart failure (CHF) causes atrial fibrotic remodeling, a substrate for atrial fibrillation (AF) maintenance. MicroRNA29 (miR29) targets extracellular matrix proteins. In the present study, we examined miR29b changes in patients with AF and/or CHF and in a CHF-related AF animal model and assessed its potential role in controlling atrial fibrous tissue production. Methods and Results— Control dogs were compared with dogs subjected to ventricular tachypacing for 24 hours, 1 week, or 2 weeks to induce CHF. Atrial miR29b expression decreased within 24 hours in both whole atrial tissue and atrial fibroblasts (−87% and −92% versus control, respectively; p <0.001 for both) and remained decreased throughout the time course. Expression of miR29b extracellular matrix target genes collagen-1A1 (COL1A1), collagen-3A1 (COL3A1), and fibrillin increased significantly in CHF fibroblasts. Lentivirus-mediated miR29b knockdown in canine atrial fibroblasts (−68%; p <0.01) enhanced COL1A1, COL3A1, and fibrillin mRNA expression by 28% ( p <0.01), 19% ( p <0.05), and 20% ( p <0.05), respectively, versus empty virus–infected fibroblasts and increased COL1A1 protein expression by 90% ( p <0.05). In contrast, 3-fold overexpression of miR29b decreased COL1A1, COL3A1, and fibrillin mRNA by 65%, 62%, and 61% (all p <0.001), respectively, versus scrambled control and decreased COL1A1 protein by 60% ( p <0.05). MiR29b plasma levels were decreased in patients with CHF or AF (by 53% and 54%, respectively; both p <0.001) and were further decreased in patients with both AF and CHF (by 84%; p <0.001). MiR29b expression was also reduced in the atria of chronic AF patients (by 54% versus sinus rhythm; p <0.05). Adenoassociated viral–mediated knockdown of miR29b in mice significantly increased atrial COL1A1 mRNA expression and cardiac tissue collagen content. Conclusions— MiR29 likely plays a role in atrial fibrotic remodeling and may have value as a biomarker and/or therapeutic target."],["dc.identifier.doi","10.1161/CIRCULATIONAHA.112.001207"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102865"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4539"],["dc.relation.issn","0009-7322"],["dc.title","MicroRNA29"],["dc.title.alternative","A Mechanistic Contributor and Potential Biomarker in Atrial Fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2955"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Journal of Clinical Investigation"],["dc.bibliographiccitation.lastpage","2968"],["dc.bibliographiccitation.volume","121"],["dc.contributor.author","Wakili, Reza"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Kääb, Stefan"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Nattel, Stanley"],["dc.date.accessioned","2022-03-01T11:43:56Z"],["dc.date.available","2022-03-01T11:43:56Z"],["dc.date.issued","2011"],["dc.identifier.doi","10.1172/JCI46315"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102877"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.issn","0021-9738"],["dc.title","Recent advances in the molecular pathophysiology of atrial fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","653"],["dc.bibliographiccitation.lastpage","675"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Makary, Samy"],["dc.contributor.author","Nattel, Stanley"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.editor","Conn, P. Michael"],["dc.date.accessioned","2022-03-01T15:25:14Z"],["dc.date.available","2022-03-01T15:25:14Z"],["dc.date.issued","2010"],["dc.description.abstract","Vagal nerve stimulation can promote atrial fibrillation (AF) that requires activation of the acetylcholine (ACh)-gated potassium current I(K,ACh). In chronic AF (cAF), I(K,ACh) shows strong activity despite the absence of ACh or analogous pharmacological stimulation. This receptor-independent, constitutive I(K,ACh) activity is suggested to represent an atrial-selective anti-AF therapeutic target, but the underlying molecular mechanisms are unknown. This chapter provides an overview of the voltage-clamp techniques that can be used to study constitutive I(K,ACh) activity in atrial myocytes and summarizes briefly the current knowledge about the potential underlying mechanism(s) of constitutive I(K,ACh) activity in diseased heart."],["dc.identifier.doi","10.1016/B978-0-12-381298-8.00032-0"],["dc.identifier.pmid","21036255"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/104010"],["dc.language.iso","en"],["dc.publisher","Elsevier"],["dc.relation.ispartof","Constitutive Activity in Receptors and Other Proteins, Part A"],["dc.title","Voltage-clamp-based methods for the detection of constitutively active acetylcholine-gated I(K,ACh) channels in the diseased heart"],["dc.type","book_chapter"],["dc.type.internalPublication","no"],["dspace.entity.type","Publication"]]