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","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","426"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Cardiovascular Research"],["dc.bibliographiccitation.lastpage","437"],["dc.bibliographiccitation.volume","74"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","FRIEDRICH, A"],["dc.contributor.author","BOCK, M"],["dc.contributor.author","WETTWER, E"],["dc.contributor.author","CHRIST, T"],["dc.contributor.author","KNAUT, M"],["dc.contributor.author","STRASSER, R"],["dc.contributor.author","RAVENS, U"],["dc.contributor.author","DOBREV, D"],["dc.date.accessioned","2022-03-01T11:45:02Z"],["dc.date.available","2022-03-01T11:45:02Z"],["dc.date.issued","2007"],["dc.identifier.doi","10.1016/j.cardiores.2007.02.009"],["dc.identifier.pii","S0008636307000594"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103191"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.issn","0008-6363"],["dc.title","Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","e162"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Cardiovascular Research"],["dc.bibliographiccitation.lastpage","e164"],["dc.bibliographiccitation.volume","116"],["dc.contributor.author","Schmidt, Constanze"],["dc.contributor.author","Voigt, Niels"],["dc.date.accessioned","2021-04-14T08:31:39Z"],["dc.date.available","2021-04-14T08:31:39Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1093/cvr/cvaa165"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83666"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/364"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A13: Bedeutung einer gestörten zytosolischen Calciumpufferung bei der atrialen Arrhythmogenese bei Patienten mit Herzinsuffizienz (HF)"],["dc.relation.eissn","1755-3245"],["dc.relation.issn","0008-6363"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.title","Insights into cardiovascular research in Göttingen and Heidelberg: a report by the ESC Scientists of Tomorrow"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","overview_ja"],["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","82"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","92"],["dc.bibliographiccitation.volume","132"],["dc.contributor.author","Schmidt, Constanze"],["dc.contributor.author","Wiedmann, Felix"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Zhou, Xiao-Bo"],["dc.contributor.author","Heijman, Jordi"],["dc.contributor.author","Lang, Siegfried"],["dc.contributor.author","Albert, Virginia"],["dc.contributor.author","Kallenberger, Stefan"],["dc.contributor.author","Ruhparwar, Arjang"],["dc.contributor.author","Szabó, Gábor"],["dc.contributor.author","Thomas, Dierk"],["dc.date.accessioned","2022-03-01T11:43:54Z"],["dc.date.available","2022-03-01T11:43:54Z"],["dc.date.issued","2015"],["dc.description.abstract","Background— Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K 2P 3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K + channel–related acid-sensitive K + channel-1]) 2-pore-domain K + (K 2P ) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Methods and Results— Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K 2P 3.1 subunits exhibited predominantly atrial expression, and atrial K 2P 3.1 transcript levels were highest among functional K 2P channels. K 2P 3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD 90 ) compared with patients in sinus rhythm. In contrast, K 2P 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K 2P 3.1 inhibition prolonged APD 90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions— Enhancement of atrium-selective K 2P 3.1 currents contributes to APD shortening in patients with chronic AF, and K 2P 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K 2P 3.1 as a novel drug target for mechanism-based AF therapy."],["dc.description.abstract","Background— Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K 2P 3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K + channel–related acid-sensitive K + channel-1]) 2-pore-domain K + (K 2P ) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Methods and Results— Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K 2P 3.1 subunits exhibited predominantly atrial expression, and atrial K 2P 3.1 transcript levels were highest among functional K 2P channels. K 2P 3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD 90 ) compared with patients in sinus rhythm. In contrast, K 2P 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K 2P 3.1 inhibition prolonged APD 90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions— Enhancement of atrium-selective K 2P 3.1 currents contributes to APD shortening in patients with chronic AF, and K 2P 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K 2P 3.1 as a novel drug target for mechanism-based AF therapy."],["dc.identifier.doi","10.1161/CIRCULATIONAHA.114.012657"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/102870"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1524-4539"],["dc.relation.issn","0009-7322"],["dc.title","Upregulation of K 2P 3.1 K + Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation"],["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","264"],["dc.bibliographiccitation.issue","04"],["dc.bibliographiccitation.journal","Deutsche medizinische Wochenschrift"],["dc.bibliographiccitation.lastpage","275"],["dc.bibliographiccitation.volume","144"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Ort, Katharina"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2020-12-10T18:12:00Z"],["dc.date.available","2020-12-10T18:12:00Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1055/a-0160-8413"],["dc.identifier.pmid","30703807"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/74209"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/252"],["dc.language.iso","de"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A13: Bedeutung einer gestörten zytosolischen Calciumpufferung bei der atrialen Arrhythmogenese bei Patienten mit Herzinsuffizienz (HF)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.title","Arzneimittelinteraktionen, die man kennen muss!"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["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"]]