Meyer-Roxlau, Stefanie

[["dc.bibliographiccitation.artnumber","e003840"],["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Circulation: Heart Failure"],["dc.bibliographiccitation.lastpage","9"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Dewenter, Matthias"],["dc.contributor.author","Neef, Stefan"],["dc.contributor.author","Vettel, Christiane"],["dc.contributor.author","Lämmle, Simon"],["dc.contributor.author","Beushausen, Christina"],["dc.contributor.author","Zelarayan, Laura C."],["dc.contributor.author","Katz, Sylvia"],["dc.contributor.author","von der Lieth, Albert"],["dc.contributor.author","Meyer-Roxlau, Stefanie"],["dc.contributor.author","Weber, Silvio"],["dc.contributor.author","Wieland, Thomas"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Backs, Johannes"],["dc.contributor.author","Brown, Joan H."],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","El-Armouche, Ali"],["dc.date.accessioned","2020-12-10T18:37:57Z"],["dc.date.available","2020-12-10T18:37:57Z"],["dc.date.issued","2017"],["dc.description.abstract","Background— Considerable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive β-adrenoceptor (β-AR) stimulation. Recent studies indicate a significant cross talk between β-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental β-AR signaling in HF. In this study, we investigated the effect of chronic β-AR blocker treatment on CaMKII activity in human and experimental HF. Methods and Results— Immunoblot analysis of myocardium from end-stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with β-AR blockers revealed no difference in CaMKII activity when compared with non–β-AR blocker–treated patients. CaMKII activity was judged by analysis of CaMKII expression, autophosphorylation, and oxidation and by investigating the phosphorylation status of CaMKII downstream targets. To further evaluate these findings, CaMKIIδC transgenic mice were treated with the β1-AR blocker metoprolol (270 mg/kg d). Metoprolol significantly reduced transgene-associated mortality (n≥29; P<0.001), attenuated the development of cardiac hypertrophy (−14±6% heart weight/tibia length; P<0.05), and strongly reduced ventricular arrhythmias (−70±22% premature ventricular contractions; P<0.05). On a molecular level, metoprolol expectedly decreased protein kinase A–dependent phospholamban and ryanodine receptor 2 phosphorylation (−42±9% for P-phospholamban-S16 and −22±7% for P-ryanodine receptor 2-S2808; P<0.05). However, this was paralled neither by a reduction in CaMKII autophosphorylation, oxidation, and substrate binding nor a change in the phosphorylation of CaMKII downstream target proteins (n≥11). The lack of CaMKII modulation by β-AR blocker treatment was confirmed in healthy wild-type mice receiving metoprolol. Conclusions— Chronic β-AR blocker therapy in patients and in a mouse model of CaMKII-induced HF is not associated with a change in CaMKII activity. Thus, our data suggest that the molecular effects of β-AR blockers are not based on a modulation of CaMKII. Directly targeting CaMKII may, therefore, further improve HF therapy in addition to β-AR blockade."],["dc.identifier.doi","10.1161/CIRCHEARTFAILURE.117.003840"],["dc.identifier.pmid","28487342"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77149"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/171"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.status","final"],["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","SFB 1002 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz"],["dc.relation.issn","1941-3289"],["dc.relation.issn","1941-3297"],["dc.relation.workinggroup","RG El-Armouche"],["dc.relation.workinggroup","RG L. Maier (Experimentelle Kardiologie)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.title","Calcium/Calmodulin-Dependent Protein Kinase II Activity Persists During Chronic β-Adrenoceptor Blockade in Experimental and Human Heart Failure"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","S67"],["dc.bibliographiccitation.journal","Naunyn-Schmiedeberg s Archives of Pharmacology"],["dc.bibliographiccitation.lastpage","S68"],["dc.bibliographiccitation.volume","387"],["dc.contributor.author","Meyer-Roxlau, Stefanie"],["dc.contributor.author","Dewenter, Matthias"],["dc.contributor.author","Vettel, Christiane"],["dc.contributor.author","El-Armouche, Ali"],["dc.date.accessioned","2018-11-07T09:44:49Z"],["dc.date.available","2018-11-07T09:44:49Z"],["dc.date.issued","2014"],["dc.identifier.isi","000359538500273"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34478"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","New york"],["dc.relation.conference","80th Annual Meeting of the Deutsche-Gesellschaft-fur-Experimentelle-und-Klinische-Pharmakologie-und Toxikologie-e-V"],["dc.relation.eventlocation","Hannover, GERMANY"],["dc.relation.issn","1432-1912"],["dc.relation.issn","0028-1298"],["dc.title","Development of molecular imaging tools to investigate protein phosphatase type-1 and type-2A localisation and dynamics in living cells"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Naunyn-Schmiedeberg s Archives of Pharmacology"],["dc.bibliographiccitation.volume","387"],["dc.contributor.author","Saadatmand, Ali Reza"],["dc.contributor.author","Dewenter, Matthias"],["dc.contributor.author","Meyer-Roxlau, Stefanie"],["dc.contributor.author","Vettel, Christiane"],["dc.contributor.author","Lehmann, Lorenz H."],["dc.contributor.author","Backs, Johannes"],["dc.contributor.author","El-Armouche, Ali"],["dc.date.accessioned","2018-11-07T09:44:50Z"],["dc.date.available","2018-11-07T09:44:50Z"],["dc.date.issued","2014"],["dc.format.extent","S80"],["dc.identifier.isi","000359538500325"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34485"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","New york"],["dc.relation.conference","80th Annual Meeting of the Deutsche-Gesellschaft-fur-Experimentelle-und-Klinische-Pharmakologie-und Toxikologie-e-V"],["dc.relation.eventlocation","Hannover, GERMANY"],["dc.relation.issn","1432-1912"],["dc.relation.issn","0028-1298"],["dc.title","PKA and CaMKII- mediated phosphorylation of Histone H3S28 during pathological b-adrenergic stimulation"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","857"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Naunyn-Schmiedeberg's Archives of Pharmacology"],["dc.bibliographiccitation.lastpage","862"],["dc.bibliographiccitation.volume","390"],["dc.contributor.author","Neef, Stefan"],["dc.contributor.author","Heijman, Jordi"],["dc.contributor.author","Otte, Kristian"],["dc.contributor.author","Dewenter, Matthias"],["dc.contributor.author","Saadatmand, Ali R."],["dc.contributor.author","Meyer-Roxlau, Stefanie"],["dc.contributor.author","Antos, Christopher L."],["dc.contributor.author","Backs, Johannes"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Wagner, Michael"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","El-Armouche, Ali"],["dc.date.accessioned","2019-02-20T15:09:24Z"],["dc.date.available","2019-02-20T15:09:24Z"],["dc.date.issued","2017"],["dc.description.abstract","Inhibitor-1 (I-1) modulates protein phosphatase 1 (PP1) activity and thereby counteracts the phosphorylation by kinases. I-1 is downregulated and deactivated in failing hearts, but whether its role is beneficial or detrimental remains controversial, and opposing therapeutic strategies have been proposed. Overactivity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) with hyperphosphorylation of ryanodine receptors (RyR2) at the CaMKII-site is recognized to be central for heart failure and arrhythmias. Using an I-1-deficient mouse line as well as transfected cell lines, we investigated the effects of acute and chronic modulation of I-1 on CaMKII activity and RyR2 phosphorylation. We demonstrate that I-1 acutely modulates CaMKII by regulating PP1 activity. However, while ablation of I-1 should thus limit CaMKII-activation, we unexpectedly found exaggerated CaMKII-activation under β-adrenergic stress upon chronic loss of I-1 in knockout mice. We unraveled that this is due to chronic upregulation of the exchange protein activated by cAMP (EPAC) leading to augmented CaMKII activation, and using computational modeling validated that an increase in EPAC expression can indeed explain our experimental findings. Interestingly, at the level of RyR2, the increase in PP1 activity more than outweighed the increase in CaMKII activity, resulting in reduced RyR phosphorylation at Ser-2814. Exaggerated CaMKII activation due to counterregulatory mechanisms upon loss of I-1 is an important caveat with respect to suggested therapeutic I-1-inhibition, as CaMKII overactivity has been heavily implicated in several cardiac pathologies."],["dc.identifier.doi","10.1007/s00210-017-1376-1"],["dc.identifier.pmid","28451724"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/57608"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/165"],["dc.language.iso","en"],["dc.notes.status","final"],["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","SFB 1002 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz"],["dc.relation.issn","0028-1298"],["dc.relation.issn","1432-1912"],["dc.relation.workinggroup","RG El-Armouche"],["dc.relation.workinggroup","RG L. Maier (Experimentelle Kardiologie)"],["dc.title","Chronic loss of inhibitor-1 diminishes cardiac RyR2 phosphorylation despite exaggerated CaMKII activity"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]