Meyer-Roxlau, Stefanie

[["dc.bibliographiccitation.artnumber","51"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","112"],["dc.contributor.author","Meyer-Roxlau, Stefanie"],["dc.contributor.author","Laemmle, Simon"],["dc.contributor.author","Opitz, Annett"],["dc.contributor.author","Kuenzel, Stephan"],["dc.contributor.author","Joos, Julius P."],["dc.contributor.author","Neef, Stefan"],["dc.contributor.author","Sekeres, Karolina"],["dc.contributor.author","Sossalla, Samuel T."],["dc.contributor.author","Schoendube, Friedrich"],["dc.contributor.author","Alexiou, Konstantin"],["dc.contributor.author","Maier, Lars. S."],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Guan, Kaomei"],["dc.contributor.author","Weber, Silvio"],["dc.contributor.author","El-Armouche, Ali"],["dc.date.accessioned","2018-11-07T10:21:50Z"],["dc.date.available","2018-11-07T10:21:50Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1007/s00395-017-0638-x"],["dc.identifier.isi","000404968800002"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42167"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Springer"],["dc.publisher.place","Heidelberg"],["dc.relation.issn","1435-1803"],["dc.relation.issn","0300-8428"],["dc.title","Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation (vol 112, pg 43, 2017)"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","43"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","112"],["dc.contributor.author","Meyer-Roxlau, Stefanie"],["dc.contributor.author","Laemmle, Simon"],["dc.contributor.author","Opitz, Annett"],["dc.contributor.author","Kuenzel, Stephan"],["dc.contributor.author","Joos, Julius P."],["dc.contributor.author","Neef, Stefan"],["dc.contributor.author","Sekeres, Karolina"],["dc.contributor.author","Sosalla, Samuel T."],["dc.contributor.author","Schoendube, Friedrich"],["dc.contributor.author","Alexiou, Konstantin"],["dc.contributor.author","Maier, Lars. S."],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Guan, Kaomei"],["dc.contributor.author","Weber, Silvio"],["dc.contributor.author","El-Armouche, Ali"],["dc.date.accessioned","2018-11-07T10:22:08Z"],["dc.date.available","2018-11-07T10:22:08Z"],["dc.date.issued","2017"],["dc.description.abstract","Protein phosphatase 1 (PP1) is a key regulator of important cardiac signaling pathways. Dysregulation of PP1 has been heavily implicated in cardiac dysfunctions. Accordingly, pharmacological targeting of PP1 activity is considered for therapeutic intervention in human cardiomyopathies. Recent evidence from animal models implicated previously unrecognized, isoform-specific activities of PP1 in the healthy and diseased heart. Therefore, this study examined the expression of the distinct PP1 isoforms PP1 alpha, beta, and gamma in human heart failure (HF) and atrial fibrillation (AF) and addressed the consequences of beta-adrenoceptor blocker (beta-blocker) therapy for HF patients with reduced ejection fraction on PP1 isoform expression. Using western blot analysis, we found greater abundance of PP1 isoforms alpha and gamma but unaltered PP1 beta levels in left ventricular myocardial tissues from HF patients as compared to non-failing controls. However, expression of all three PP1 isoforms was higher in atrial appendages from patients with AF compared to patients with sinus rhythm. Moreover, we found that in human failing ventricles, beta-blocker therapy was associated with lower PP1 alpha abundance and activity, as indicated by higher phosphorylation of the PP1 alpha-specific substrate eIF2 alpha. Greater eIF2 alpha phosphorylation is a known repressor of protein translation, and accordingly, we found lower levels of the endoplasmic reticulum (ER) stress marker Grp78 in the very same samples. We propose that isoform-specific targeting of PP1 alpha activity may be a novel and innovative therapeutic strategy for the treatment of human cardiac diseases by reducing ER stress conditions."],["dc.identifier.doi","10.1007/s00395-017-0635-0"],["dc.identifier.isi","000403282500003"],["dc.identifier.pmid","28597249"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42221"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Springer"],["dc.publisher.place","Heidelberg"],["dc.relation.issn","1435-1803"],["dc.relation.issn","0300-8428"],["dc.title","Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["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","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"]]