Eiringhaus, Jörg

[["dc.bibliographiccitation.firstpage","719"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Artificial Organs"],["dc.bibliographiccitation.lastpage","726"],["dc.bibliographiccitation.volume","40"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Kleinwächter, Astrid"],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Eiringhaus, Jörg"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Haverich, Axel"],["dc.contributor.author","Schmitto, Jan D."],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2018-11-07T10:10:45Z"],["dc.date.available","2018-11-07T10:10:45Z"],["dc.date.issued","2016"],["dc.description.abstract","In heart failure, left ventricular assist device (LVAD) implantation is performed to ensure sufficient cardiac output. Whereas some patients are subsequently weaned from LVAD support, other patients still need heart transplantation. To elucidate underlying mechanisms, we assessed the arrhythmogenic SR-Ca2+ leak at the time of LVAD implantation (HF-Im) and heart transplantation (HF-Tx) and evaluated the effects of CaMKII-inhibition. Human left-ventricular cardiomyocytes were isolated, paced at 1Hz for 10 beats to ensure SR-Ca2+ loading and scanned for diastolic Ca2+ sparks (confocal microscopy). In HF-Im, the high diastolic spark frequency (CaSpF) of 0.76 +/- 0.12x100m(-1)xs(-1) could be reduced to 0.48 +/- 0.10x100m(-1)xs(-1) by CaMKII inhibition (AIP, 1M). The amplitude of Ca2+ sparks, width, and length was not significantly altered. In sum, CaMKII inhibition yielded a clear tendency toward a reduction of the SR-Ca2+ leak (n cells/patients=76/6 vs. 108/6, P=0.08). In HF-Tx, we detected an even higher CaSpF of 1.00 +/- 0.10 100m(-1)xs(-1) and a higher SR-Ca2+ leak compared with HF-Im (increase by 81 +/- 33%, n cells/patients=156/7 vs. 130/7, P<0.05), which fits to the further decreased LV function. Here, CaMKII inhibition likewise reduced CaSpF (0.35 +/- 0.09 100m(-1)xs(-1,)P=0.06) and significantly reduced spark duration (n sparks/patients=58/3 vs. 159/3, P<0.05). Conclusively, the SR-Ca2+ leak was reduced by 69 +/- 12% in HF-Tx upon CaMKII inhibition (n cells/patients=53/3 vs. 91/3, P<0.05). These data show that the SR-Ca2+ leak correlates with the development of LV function after LVAD implantation and may represent an important pathomechanism. The fact that CaMKII inhibition reduces the SR-Ca2+ leak in HF-Tx suggests that CaMKII inhibition may be a promising option to beneficially influence clinical course after LVAD implantation."],["dc.identifier.doi","10.1111/aor.12677"],["dc.identifier.isi","000383514300005"],["dc.identifier.pmid","26816346"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39920"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/136"],["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","1525-1594"],["dc.relation.issn","0160-564X"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.title","Inhibition of CaMKII Attenuates Progressing Disruption of Ca2+ Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Der Internist"],["dc.bibliographiccitation.volume","57"],["dc.contributor.author","Herting, J. Jonas"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Eiringhaus, Joerg"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Sossalla, Samuel T."],["dc.contributor.author","Fischer, T."],["dc.date.accessioned","2018-11-07T10:15:51Z"],["dc.date.available","2018-11-07T10:15:51Z"],["dc.date.issued","2016"],["dc.format.extent","S20"],["dc.identifier.isi","000375417500035"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40900"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","New york"],["dc.relation.issn","1432-1289"],["dc.relation.issn","0020-9554"],["dc.title","Influence of Atrial Fibrillation on the electromechanical Coupling in human Ventricular Myocardium"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","European Journal of Heart Failure"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Herting, J. Jonas"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Eiringhaus, Joerg"],["dc.contributor.author","Pabel, Stefanie Corinna"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Sossalla, Samuel T."],["dc.contributor.author","Fischer, Thomas H."],["dc.date.accessioned","2018-11-07T10:14:46Z"],["dc.date.available","2018-11-07T10:14:46Z"],["dc.date.issued","2016"],["dc.format.extent","515"],["dc.identifier.isi","000377107504258"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40681"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-blackwell"],["dc.publisher.place","Hoboken"],["dc.relation.issn","1879-0844"],["dc.relation.issn","1388-9842"],["dc.title","Effects of atrial fibrillation on ventricular calcium cycling in human myocardium"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","European Heart Journal"],["dc.bibliographiccitation.volume","35"],["dc.contributor.author","Eiringhaus, Joerg"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Herting, J. Jonas"],["dc.contributor.author","Schmitto, J."],["dc.contributor.author","Foerster, A."],["dc.contributor.author","Renner, Andre"],["dc.contributor.author","Gummert, J. F."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Maier, Lars. S."],["dc.contributor.author","Sossalla, Samuel T."],["dc.date.accessioned","2018-11-07T09:35:32Z"],["dc.date.available","2018-11-07T09:35:32Z"],["dc.date.issued","2014"],["dc.format.extent","328"],["dc.identifier.isi","000343001302012"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/32409"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.publisher.place","Oxford"],["dc.relation.eventlocation","Barcelona, SPAIN"],["dc.relation.issn","1522-9645"],["dc.relation.issn","0195-668X"],["dc.title","CaMKII equally triggers SR Ca2+leak in human ischemic and non-ischemic heart failure"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1673"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","European Journal of Heart Failure"],["dc.bibliographiccitation.lastpage","1685"],["dc.bibliographiccitation.volume","20"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Eiringhaus, Jörg"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Saadatmand, Alireza"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Weber, Silvio"],["dc.contributor.author","Wang, Yansong"],["dc.contributor.author","Köhn, Maja"],["dc.contributor.author","Tirilomis, Theodor"],["dc.contributor.author","Ljubojevic, Senka"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2019-02-18T13:43:31Z"],["dc.date.available","2019-02-18T13:43:31Z"],["dc.date.issued","2018"],["dc.description.abstract","Background Disruption of Ca2+ homeostasis is a key pathomechanism in heart failure. CaMKII-dependent hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum (SR) increases the arrhythmogenic SR Ca2+ leak and depletes SR Ca2+ stores. The contribution of conversely acting serine/threonine phosphatases [protein phosphatase 1 (PP1) and 2A (PP2A)] is largely unknown. Methods and results Human myocardium from three groups of patients was investigated: (i) healthy controls (non-failing, NF, n = 8), (ii) compensated hypertrophy (Hy, n = 16), and (iii) end-stage heart failure (HF, n = 52). Expression of PP1 was unchanged in Hy but greater in HF compared to NF while its endogenous inhibitor-1 (I-1) was markedly lower expressed in both compared to NF, suggesting increased total PP1 activity. In contrast, PP2A expression was lower in Hy and HF compared to NF. Ca2+ homeostasis was severely disturbed in HF compared to Hy signified by a higher SR Ca2+ leak, lower systolic Ca2+ transients as well as a decreased SR Ca2+ load. Inhibition of PP1/PP2A by okadaic acid increased SR Ca2+ load and systolic Ca2+ transients but severely aggravated diastolic SR Ca2+ leak and cellular arrhythmias in Hy. Conversely, selective activation of PP1 by a PP1-disrupting peptide (PDP3) in HF potently reduced SR Ca2+ leak as well as cellular arrhythmias and, importantly, did not compromise systolic Ca2+ release and SR Ca2+ load. Conclusion This study is the first to functionally investigate the role of PP1/PP2A for Ca2+ homeostasis in diseased human myocardium. Our data indicate that a modulation of phosphatase activity potently impacts Ca2+ cycling properties. An activation of PP1 counteracts increased kinase activity in heart failure and successfully seals the arrhythmogenic SR Ca2+ leak. It may thus represent a promising future antiarrhythmic therapeutic approach."],["dc.identifier.doi","10.1002/ejhf.1297"],["dc.identifier.pmid","30191648"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/57579"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/232"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A11: Absolute Arrhythmie bei Vorhofflimmern - ein neuer Mechanismus, der zu einer Störung von Ca2+-Homöostase und elektrischer Stabilität in der Transition zur Herzinsuffizienz führt"],["dc.relation.issn","1879-0844"],["dc.relation.workinggroup","RG El-Armouche"],["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.title","Activation of protein phosphatase 1 by a selective phosphatase disrupting peptide reduces sarcoplasmic reticulum Ca2+ leak in human heart failure"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","13"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","114"],["dc.contributor.author","Eiringhaus, Jörg"],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Schatter, Felix"],["dc.contributor.author","Nikolaev, Viacheslav O."],["dc.contributor.author","Sprenger, Julia"],["dc.contributor.author","Wang, Yansong"],["dc.contributor.author","Köhn, Maja"],["dc.contributor.author","Zabel, Markus"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Fischer, Thomas H."],["dc.date.accessioned","2019-08-02T06:17:58Z"],["dc.date.available","2019-08-02T06:17:58Z"],["dc.date.issued","2019"],["dc.description.abstract","Increased late sodium current (late INa) is an important arrhythmogenic trigger in cardiac disease. It prolongs cardiac action potential and leads to an increased SR Ca2+ leak. This study investigates the contribution of Ca2+/Calmodulin-dependent kinase II (CaMKII), protein kinase A (PKA) and conversely acting protein phosphatases 1 and 2A (PP1, PP2A) to this subcellular crosstalk. Augmentation of late INa (ATX-II) in murine cardiomyocytes led to an increase of diastolic Ca2+ spark frequency and amplitudes of Ca2+ transients but did not affect SR Ca2+ load. Interestingly, inhibition of both, CaMKII and PKA, attenuated the late INa-dependent induction of the SR Ca2+ leak. PKA inhibition additionally reduced the amplitudes of systolic Ca2+ transients. FRET-measurements revealed increased levels of cAMP upon late INa augmentation, which could be prevented by simultaneous inhibition of Na+/Ca2+-exchanger (NCX) suggesting that PKA is activated by Ca2+-dependent cAMP-production. Whereas inhibition of PP2A showed no effect on late INa-dependent alterations of Ca2+ cycling, additional inhibition of PP1 further increased the SR Ca2+ leak. In line with this, selective activation of PP1 yielded a strong reduction of the late INa-induced SR Ca2+ leak and did not affect systolic Ca2+ release. This study indicates that phosphatase/kinase-balance is perturbed upon increased Na+ influx leading to disruption of ventricular Ca2+ cycling via CaMKII- and PKA-dependent pathways. Importantly, an activation of PP1 at RyR2 may represent a promising new toehold to counteract pathologically increased kinase activity."],["dc.identifier.doi","10.1007/s00395-019-0720-7"],["dc.identifier.pmid","30788598"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/62260"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/256"],["dc.language.iso","en"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A11: Absolute Arrhythmie bei Vorhofflimmern - ein neuer Mechanismus, der zu einer Störung von Ca2+-Homöostase und elektrischer Stabilität in der Transition zur Herzinsuffizienz führt"],["dc.relation.eissn","1435-1803"],["dc.relation.issn","0300-8428"],["dc.relation.issn","1435-1803"],["dc.relation.workinggroup","RG El-Armouche"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["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","Protein kinase/phosphatase balance mediates the effects of increased late sodium current on ventricular calcium cycling"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","European Heart Journal"],["dc.bibliographiccitation.volume","36"],["dc.contributor.author","Eiringhaus, Joerg"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Saadatmand, Ali Reza"],["dc.contributor.author","Singh, S."],["dc.contributor.author","Kohn, M."],["dc.contributor.author","Wang, Y."],["dc.contributor.author","Maier, Lars. S."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Sossalla, Samuel T."],["dc.date.accessioned","2018-11-07T09:53:30Z"],["dc.date.available","2018-11-07T09:53:30Z"],["dc.date.issued","2015"],["dc.format.extent","362"],["dc.identifier.isi","000361205103090"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36341"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.publisher.place","Oxford"],["dc.relation.eventlocation","London, ENGLAND"],["dc.relation.issn","1522-9645"],["dc.relation.issn","0195-668X"],["dc.title","Ca-homeostasis in human cardiac hypertrophy and end stage heart failure is directly impacted by modulations of protein phosphatase 1 and-2a activity"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Der Internist"],["dc.bibliographiccitation.volume","57"],["dc.contributor.author","Eiringhaus, Joerg"],["dc.contributor.author","Herting, J. Jonas"],["dc.contributor.author","Schatter, F."],["dc.contributor.author","Koehn, M."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Sossalla, Samuel T."],["dc.contributor.author","Fischer, T."],["dc.date.accessioned","2018-11-07T10:15:50Z"],["dc.date.available","2018-11-07T10:15:50Z"],["dc.date.issued","2016"],["dc.format.extent","S60"],["dc.identifier.isi","000375417500119"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40897"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","New york"],["dc.relation.issn","1432-1289"],["dc.relation.issn","0020-9554"],["dc.title","Induction Mechanisms of SR-Calcium-Leaks through the late Sodium Current in ventricular Myocardium"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1440"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","EP Europace"],["dc.bibliographiccitation.lastpage","1448"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Eiringhaus, Jörg"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Hartmann, Nico H."],["dc.contributor.author","Ellenberger, David"],["dc.contributor.author","Friedrich, Martin"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Zabel, Markus"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2017-09-07T11:44:40Z"],["dc.date.available","2017-09-07T11:44:40Z"],["dc.date.issued","2016"],["dc.description.abstract","Aims Clinical studies have shown differences in the propensity for malignant ventricular arrhythmias between women and men suffering from cardiomyopathies and heart failure (HF). This is clinically relevant as it impacts therapies like prophylactic implantable cardioverter-defibrillator implantation but the pathomechanisms are unknown. As an increased sarcoplasmic reticulum (SR) Ca2+ leak is arrhythmogenic, it could represent a cellular basis for this paradox. Methods/Results We evaluated the SR Ca2+ leak with respect to sex differences in (i) afterload-induced cardiac hypertrophy (Hy) with preserved left ventricular (LV) function and (ii) end-stage HF. Cardiac function did not differ between sexes in both cardiac pathologies. Human cardiomyocytes isolated from female patients with Hy showed a significantly lower Ca2+ spark frequency (CaSpF, confocal microscopy, Fluo3-AM) compared with men (P < 0.05). As Ca2+ spark width and duration were similar in women and men, this difference in CaSpF did not yet translate into a significant difference of the calculated SR Ca2+ leak between both sexes at this stage of disease (P < 0.14). Epifluorescence measurements (Fura2-AM) revealed comparable Ca2+ cycling properties (diastolic Ca2+ levels, amplitude of systolic Ca2+ transients, SR Ca2+ load) in patients of both sexes suffering from Hy. Additionally, the increased diastolic CaSpF in male patients with Hy did not yet translate into an elevated ratio of cells showing arrhythmic events (Ca2+ waves, spontaneous Ca2+ transients) (P < 0.77). In the transition to HF, both sexes showed an increase of the CaSpF (P, 0.05) and the sex dependence was even more pronounced. Female patients had a 69 +/- 10% lower SR Ca2+ leak (P < 0.05), which now even translated into a lower ratio of arrhythmic cells in female HF patients compared with men (P < 0.001). Conclusion These data show that the SR Ca2+ leak is lower in women than in men with comparable cardiac impairment. Since the SR Ca2+ leak triggers delayed afterdepolarizations, our findings may explain why women are less prone to ventricular arrhythmias and confirm the rationale of therapeutic measures reducing the SR Ca2+ leak."],["dc.identifier.doi","10.1093/europace/euv313"],["dc.identifier.gro","3141624"],["dc.identifier.isi","000387007900027"],["dc.identifier.pmid","26493982"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2455"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/96"],["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","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation.issn","1099-5129"],["dc.relation.issn","1532-2092"],["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.title","Sex-dependent alterations of Ca2+ cycling in human cardiac hypertrophy and heart failure"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","P5841"],["dc.bibliographiccitation.firstpage","1236"],["dc.bibliographiccitation.issue","suppl_1"],["dc.bibliographiccitation.journal","European Heart Journal"],["dc.bibliographiccitation.volume","38"],["dc.contributor.author","Eiringhaus, J."],["dc.contributor.author","Fischer, T. H."],["dc.contributor.author","Kohn, M."],["dc.contributor.author","Wang, Y."],["dc.contributor.author","Maier, L. S."],["dc.contributor.author","Hasenfuss, G."],["dc.contributor.author","Sossalla, S. T."],["dc.date.accessioned","2019-02-18T14:31:03Z"],["dc.date.available","2019-02-18T14:31:03Z"],["dc.date.issued","2017"],["dc.description.abstract","Background Disruption of Ca2+ homeostasis is a key pathomechanism in heart failure. CaMKII‐dependent hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum (SR) increases the arrhythmogenic SR Ca2+ leak and depletes SR Ca2+ stores. The contribution of conversely acting serine/threonine phosphatases [protein phosphatase 1 (PP1) and 2A (PP2A)] is largely unknown. Methods and results Human myocardium from three groups of patients was investigated: (i) healthy controls (non‐failing, NF, n = 8), (ii) compensated hypertrophy (Hy, n = 16), and (iii) end‐stage heart failure (HF, n = 52). Expression of PP1 was unchanged in Hy but greater in HF compared to NF while its endogenous inhibitor‐1 (I‐1) was markedly lower expressed in both compared to NF, suggesting increased total PP1 activity. In contrast, PP2A expression was lower in Hy and HF compared to NF. Ca2+ homeostasis was severely disturbed in HF compared to Hy signified by a higher SR Ca2+ leak, lower systolic Ca2+ transients as well as a decreased SR Ca2+ load. Inhibition of PP1/PP2A by okadaic acid increased SR Ca2+ load and systolic Ca2+ transients but severely aggravated diastolic SR Ca2+ leak and cellular arrhythmias in Hy. Conversely, selective activation of PP1 by a PP1‐disrupting peptide (PDP3) in HF potently reduced SR Ca2+ leak as well as cellular arrhythmias and, importantly, did not compromise systolic Ca2+ release and SR Ca2+ load. Conclusion This study is the first to functionally investigate the role of PP1/PP2A for Ca2+ homeostasis in diseased human myocardium. Our data indicate that a modulation of phosphatase activity potently impacts Ca2+ cycling properties. An activation of PP1 counteracts increased kinase activity in heart failure and successfully seals the arrhythmogenic SR Ca2+ leak. It may thus represent a promising future antiarrhythmic therapeutic approach."],["dc.identifier.doi","10.1093/eurheartj/ehx493.P5841"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/57581"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/180"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation.issn","0195-668X"],["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.title","PP1 activation as novel antiarrhythmic approach in human heart failure"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]