Mason, Fleur E.

[["dc.bibliographiccitation.firstpage","599a"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Biophysical Journal"],["dc.bibliographiccitation.volume","110"],["dc.contributor.author","Lindner, Marta"],["dc.contributor.author","Vettel, Christiane"],["dc.contributor.author","Dewenter, Matthias"],["dc.contributor.author","Riedel, Merle"],["dc.contributor.author","Lämmle, Simon"],["dc.contributor.author","Mason, Fleur"],["dc.contributor.author","Meinecke, Simon"],["dc.contributor.author","Wieland, Thomas"],["dc.contributor.author","Mehel, Hind"],["dc.contributor.author","Karam, Sarah"],["dc.contributor.author","Lechene, Patrick"],["dc.contributor.author","Leroy, Jerome"],["dc.contributor.author","Vandecasteele, Gregoire"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Fischmeister, Rodolphe"],["dc.date.accessioned","2020-12-10T14:22:42Z"],["dc.date.available","2020-12-10T14:22:42Z"],["dc.date.issued","2016"],["dc.identifier.doi","10.1016/j.bpj.2015.11.3199"],["dc.identifier.issn","0006-3495"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/71701"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","Cardiac-Specific Overexpression of Phosphodiesterase 2 (PDE2) in Mouse is Cardioprotective"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

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

[["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","115"],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Pronto, Julius Ryan D."],["dc.contributor.author","Alhussini, Khaled"],["dc.contributor.author","Maack, Christoph"],["dc.contributor.author","Voigt, Niels"],["dc.date.accessioned","2021-04-14T08:30:49Z"],["dc.date.available","2021-04-14T08:30:49Z"],["dc.date.issued","2020"],["dc.description.abstract","The molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation–contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF."],["dc.identifier.doi","10.1007/s00395-020-00827-7"],["dc.identifier.pmid","33258071"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83381"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/137"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/379"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["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","1435-1803"],["dc.relation.issn","0300-8428"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.rights","CC BY 4.0"],["dc.title","Cellular and mitochondrial mechanisms of atrial fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","overview_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","40"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Journal of Cardiovascular Pharmacology and Therapeutics"],["dc.bibliographiccitation.lastpage","50"],["dc.bibliographiccitation.volume","22"],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2018-11-07T10:29:06Z"],["dc.date.available","2018-11-07T10:29:06Z"],["dc.date.issued","2017"],["dc.description.abstract","The purpose of this article is to review the basis of arrhythmogenesis, the functional and clinical role of the late Na current, and its therapeutic inhibition. Under pathological conditions such as ischemia and heart failure this current is abnormally enhanced and influences cellular electrophysiology as a proarrhythmic substrate in myocardial pathology. Ranolazine the only approved late Na current blocker has been demonstrated to produce antiarrhythmic effects in the atria and the ventricle. We summarize recent experimental and clinical studies of ranolazine and other experimental late Na current blockers and discuss the significance of the available data."],["dc.identifier.doi","10.1177/1074248416644989"],["dc.identifier.isi","000393946900004"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43567"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/147"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["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","1940-4034"],["dc.relation.issn","1074-2484"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.title","The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","overview_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","184"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cardiovascular Research"],["dc.bibliographiccitation.lastpage","196"],["dc.bibliographiccitation.volume","107"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Watanabe, Saera"],["dc.contributor.author","Nikolaev, Viacheslav O."],["dc.contributor.author","Sprenger, Julia U."],["dc.contributor.author","Fan, Peidong"],["dc.contributor.author","Yao, Lina"],["dc.contributor.author","Popov, Aron-Frederik"],["dc.contributor.author","Danner, Bernhard C."],["dc.contributor.author","Schoendube, Friedrich"],["dc.contributor.author","Belardinelli, Luiz"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2017-09-07T11:43:42Z"],["dc.date.available","2017-09-07T11:43:42Z"],["dc.date.issued","2015"],["dc.description.abstract","Aims Enhanced cardiac late Na current (late I-Na) and increased sarcoplasmic reticulum (SR)-Ca2+-leak are both highly arrhythmogenic. This study seeks to identify signalling pathways interconnecting late I-Na and SR-Ca2+-leak in atrial cardiomyocytes (CMs). Methods and results In murine atrial CMs, SR-Ca2+-leak was increased by the late I-Na enhancer Anemonia sulcata toxin II (ATX-II). An inhibition of Ca2+/calmodulin-dependent protein kinase II (Autocamide-2-related inhibitory peptide), protein kinase A (H89), or late I-Na (Ranolazine or Tetrodotoxin) all prevented ATX-II-dependent SR-Ca2+-leak. The SR-Ca2+-leak induction by ATX-II was not detected when either the Na+/Ca2+ exchanger was inhibited (KBR) or in CaMKIIdc-knockout mice. FRET measurements revealed increased cAMP levels upon ATX-II stimulation, which could be prevented by inhibition of adenylyl cyclases (ACs) 5 and 6 (NKY 80) but not by inhibition of phosphodiesterases (IBMX), suggesting PKA activation via an AC-dependent increase of cAMP levels. Western blots showed late I-Na-dependent hyperphosphorylation of CaMKII as well as PKA target sites at ryanodine receptor type-2 (-S2814 and -S2808) and phospholamban (-Thr17, -S16). Enhancement of late I-Na did not alter Ca2+-transient amplitude or SR-Ca2+-load. However, upon late I-Na activation and simultaneous CaMKII inhibition, Ca2+-transient amplitude and SR-Ca2+-load were increased, whereas PKA inhibition reduced Ca2+-transient amplitude and load and additionally slowed Ca2+ elimination. In atrial CMs from patients with atrial fibrillation, inhibition of late I-Na, CaMKII, or PKA reduced the SR-Ca2+-leak. Conclusion Late I-Na exerts distinct effects on Ca2+ homeostasis in atrial myocardium through activation of CaMKII and PKA. Inhibition of late I-Na represents a potential approach to attenuate CaMKII activation and decreases SR-Ca2+-leak in atrial rhythm disorders. The interconnection with the cAMP/PKA system further increases the antiarrhythmic potential of late I-Na inhibition."],["dc.identifier.doi","10.1093/cvr/cvv153"],["dc.identifier.gro","3141867"],["dc.identifier.isi","000359088800021"],["dc.identifier.pmid","25990311"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1956"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/104"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz"],["dc.relation.eissn","1755-3245"],["dc.relation.issn","0008-6363"],["dc.relation.issn","1755-3245"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG L. Maier (Experimentelle Kardiologie)"],["dc.relation.workinggroup","RG Nikolaev (Cardiovascular Research Center)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.title","Late INa increases diastolic SR-Ca2+-leak in atrial myocardium by activating PKA and CaMKII"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","120"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Circulation Research"],["dc.bibliographiccitation.lastpage","132"],["dc.bibliographiccitation.volume","120"],["dc.contributor.author","Vettel, Christiane"],["dc.contributor.author","Lindner, Marta"],["dc.contributor.author","Dewenter, Matthias"],["dc.contributor.author","Lorenz, Kristina"],["dc.contributor.author","Schanbacher, Constanze"],["dc.contributor.author","Riedel, Merle"],["dc.contributor.author","Lämmle, Simon"],["dc.contributor.author","Meinecke, Simone"],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Geerts, Andreas"],["dc.contributor.author","Hoffmann, Michael"],["dc.contributor.author","Wunder, Frank"],["dc.contributor.author","Brunner, Fabian J."],["dc.contributor.author","Wieland, Thomas"],["dc.contributor.author","Mehel, Hind"],["dc.contributor.author","Karam, Sarah"],["dc.contributor.author","Lechêne, Patrick"],["dc.contributor.author","Leroy, Jérôme"],["dc.contributor.author","Vandecasteele, Grégoire"],["dc.contributor.author","Wagner, Michael"],["dc.contributor.author","Fischmeister, Rodolphe"],["dc.contributor.author","El-Armouche, Ali"],["dc.date.accessioned","2020-12-10T18:37:59Z"],["dc.date.available","2020-12-10T18:37:59Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1161/CIRCRESAHA.116.310069"],["dc.identifier.pmid","27799254"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77159"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/309"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A02: Bedeutung des Phosphatase-Inhibitors-1 für die SR-spezifische Modulation der Beta- adrenozeptor-Signalkaskade"],["dc.relation.workinggroup","RG El-Armouche"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.title","Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Herzschrittmachertherapie + Elektrophysiologie"],["dc.bibliographiccitation.lastpage","13"],["dc.bibliographiccitation.volume","29"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Mason, Fleur"],["dc.contributor.author","Thomas, Dierk"],["dc.date.accessioned","2021-06-01T10:49:11Z"],["dc.date.available","2021-06-01T10:49:11Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1007/s00399-017-0549-4"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/86196"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.relation.eissn","1435-1544"],["dc.relation.issn","0938-7412"],["dc.title","Report on the Ion Channel Symposium Organized by the German Cardiac Society Working Group on Cellular Electrophysiology (AG 18)"],["dc.title.translated","Bericht vom Ionenkanal-Symposium"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4816"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","International Journal of Molecular Sciences"],["dc.bibliographiccitation.volume","22"],["dc.contributor.affiliation","Wagner, Michael; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, michael_wagner@tu-dresden.de\t\t \r\n\t\t Klinik für Innere Medizin und Kardiologie, Dresden Heart Center, Dresden University of Technology, 01307 Dresden, Germany, michael_wagner@tu-dresden.de"],["dc.contributor.affiliation","Sadek, Mirna S.; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, mirna.sadeks@gmail.com"],["dc.contributor.affiliation","Dybkova, Nataliya; \t\t \r\n\t\t Clinic for Cardiology & Pneumology, University of Göttingen, 37075 Göttingen, Germany, ndybkov@med.uni-goettingen.de\t\t \r\n\t\t DZHK (German Centre for Cardiovascular Research), 10785 Berlin, Germany, ndybkov@med.uni-goettingen.de"],["dc.contributor.affiliation","Mason, Fleur E.; \t\t \r\n\t\t Clinic for Cardiology & Pneumology, University of Göttingen, 37075 Göttingen, Germany, fleur.mason@med.uni-goettingen.de\t\t \r\n\t\t DZHK (German Centre for Cardiovascular Research), 10785 Berlin, Germany, fleur.mason@med.uni-goettingen.de"],["dc.contributor.affiliation","Klehr, Johann; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, johann.klehr@tu-dresden.de"],["dc.contributor.affiliation","Firneburg, Rebecca; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, rebecca.firneburg@tu-dresden.de"],["dc.contributor.affiliation","Cachorro, Eleder; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, eleder.cachorro_puente@tu-dresden.de"],["dc.contributor.affiliation","Richter, Kurt; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, kurt.richter@outlook.de\t\t \r\n\t\t Klinik für Innere Medizin und Kardiologie, Dresden Heart Center, Dresden University of Technology, 01307 Dresden, Germany, kurt.richter@outlook.de"],["dc.contributor.affiliation","Klapproth, Erik; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, erik.klapproth@tu-dresden.de"],["dc.contributor.affiliation","Kuenzel, Stephan R.; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, Stephan.kuenzel@tu-dresden.de"],["dc.contributor.affiliation","Lorenz, Kristina; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Julius-Maximilians-Universität Würzburg, 97078 Würzburg, Germany, lorenz@toxi.uni-wuerzburg.de\t\t \r\n\t\t Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany, lorenz@toxi.uni-wuerzburg.de"],["dc.contributor.affiliation","Heijman, Jordi; \t\t \r\n\t\t Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine, and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands, Jordi.heijman@maastrichtuniversity.nl"],["dc.contributor.affiliation","Dobrev, Dobromir; \t\t \r\n\t\t Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, 45147 Essen, Germany, Dobromir.dobrev@uk-essen.de\t\t \r\n\t\t Montréal Heart Institute, Research Center, University de Montréal, Montréal, QC H1T 1C8, Canada, Dobromir.dobrev@uk-essen.de\t\t \r\n\t\t Department of Molecular Physiology Biophysics, Baylor College of Medicine, Houston, TX 77030, USA, Dobromir.dobrev@uk-essen.de"],["dc.contributor.affiliation","El-Armouche, Ali; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, ali.el-armouche@tu-dresden.de"],["dc.contributor.affiliation","Sossalla, Samuel; \t\t \r\n\t\t Clinic for Cardiology & Pneumology, University of Göttingen, 37075 Göttingen, Germany, samuel.sossalla@ukr.de\t\t \r\n\t\t DZHK (German Centre for Cardiovascular Research), 10785 Berlin, Germany, samuel.sossalla@ukr.de\t\t \r\n\t\t Department of Internal Medicine II, University Hospital Regensburg, 93042 Regensburg, Germany, samuel.sossalla@ukr.de"],["dc.contributor.affiliation","Kämmerer, Susanne; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, susanne.kaemmerer@tu-dresden.de"],["dc.contributor.author","Wagner, Michael"],["dc.contributor.author","Sadek, Mirna S."],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Klehr, Johann"],["dc.contributor.author","Firneburg, Rebecca"],["dc.contributor.author","Cachorro, Eleder"],["dc.contributor.author","Richter, Kurt"],["dc.contributor.author","Klapproth, Erik"],["dc.contributor.author","Kämmerer, Susanne"],["dc.contributor.author","Kuenzel, Stephan R."],["dc.contributor.author","Lorenz, Kristina"],["dc.contributor.author","Heijman, Jordi"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2021-06-01T09:42:36Z"],["dc.date.available","2021-06-01T09:42:36Z"],["dc.date.issued","2021"],["dc.date.updated","2022-11-11T13:15:11Z"],["dc.description.abstract","Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca2+-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in ICaL seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in INaL and Ca2+-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF."],["dc.description.sponsorship","German Research Foundation"],["dc.identifier.doi","10.3390/ijms22094816"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85300"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.publisher","MDPI"],["dc.relation.eissn","1422-0067"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0/"],["dc.title","Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]