Eschenhagen, Thomas

[["dc.bibliographiccitation.firstpage","87"],["dc.bibliographiccitation.journal","IJC Heart & Vasculature"],["dc.bibliographiccitation.lastpage","94"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Friedrich, Felix W."],["dc.contributor.author","Sotoud, Hannieh"],["dc.contributor.author","Geertz, Birgit"],["dc.contributor.author","Weber, Silvio"],["dc.contributor.author","Flenner, Frederik"],["dc.contributor.author","Reischmann, Silke"],["dc.contributor.author","Eschenhagen, Thomas"],["dc.contributor.author","Carrier, Lucie"],["dc.contributor.author","El-Armouche, Ali"],["dc.date.accessioned","2019-01-17T16:01:00Z"],["dc.date.available","2019-01-17T16:01:00Z"],["dc.date.issued","2015"],["dc.description.abstract","Aims Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction and increased interstitial fibrosis. Current treatment is based on beta-adrenoceptor (AR) and calcium channel blockers. Since mice deficient of protein phosphatase-1 inhibitor-1 (I-1), an amplifier in beta-AR signalling, were protected from pathological adrenergic stimulation in vivo, we hypothesized that I-1 ablation could result in an improved outcome in a HCM mouse model. Methods and results We crossed mice deficient of I-1 with homozygous myosin-binding protein C knock-out (Mybpc3 KO) mice exhibiting cardiac dilatation and reduced survival. Unexpectedly, survival time was shorter in double I-1/Mybpc3 KO than in single Mybpc3 KO mice. Longitudinal echocardiographic assessment revealed lower fractional area change, and higher diastolic left ventricular inner dimensions and end-diastolic volumes in Mybpc3 KO than in WT mice. In comparison to Mybpc3 KO, double I-1/Mybpc3 KO presented higher left ventricular end-diastolic volumes, inner dimensions and ventricular surface areas with increasing differences over time. Phosphorylation levels of PKA-downstream targets and mRNA levels of hypertrophic markers did not differ between I-1/Mybpc3 KO and single Mybpc3 KO mice, except a trend towards higher beta-myosin heavy chain levels in double I-1/Mybpc3 KO. Conclusion The data indicate that interference with beta-AR signalling has no long-term benefit in this severe MYBPC3-related cardiomyopathy mouse model."],["dc.identifier.doi","10.1016/j.ijcha.2015.05.010"],["dc.identifier.pmid","28785686"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/57350"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/87"],["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.issn","2352-9067"],["dc.relation.workinggroup","RG El-Armouche"],["dc.rights","CC BY-NC-ND 4.0"],["dc.title","I-1-deficiency negatively impacts survival in a cardiomyopathy mouse model"],["dc.type","journal_article"],["dc.type.internalPublication","no"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e98893"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","PLOS ONE"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Neuber, Christiane"],["dc.contributor.author","Uebeler, June"],["dc.contributor.author","Schulze, Thomas"],["dc.contributor.author","Sotoud, Hannieh"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Eschenhagen, Thomas"],["dc.date.accessioned","2018-11-07T09:39:00Z"],["dc.date.available","2018-11-07T09:39:00Z"],["dc.date.issued","2014"],["dc.description.abstract","Endoplasmic reticulum (ER) stress has been implicated in a variety of cardiovascular diseases. During ER stress, disruption of the complex of protein phosphatase 1 regulatory subunit 15A and catalytic subunit of protein phosphatase 1 by the small molecule guanabenz (antihypertensive, alpha(2)-adrenoceptor agonist) and subsequent inhibition of stress-induced dephosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2 alpha) results in prolonged eIF2 alpha phosphorylation, inhibition of protein synthesis and protection from ER stress. In this study we assessed whether guanabenz protects against ER stress in cardiac myocytes and affects the function of 3 dimensional engineered heart tissue (EHT). We utilized neonatal rat cardiac myocytes for the assessment of cell viability and activation of ER stress-signalling pathways and EHT for functional analysis. (i) Tunicamycin induced ER stress as measured by increased mRNA and protein levels of glucose-regulated protein 78 kDa, P-eIF2 alpha, activating transcription factor 4, C/EBP homologous protein, and cell death. (ii) Guanabenz had no measurable effect alone, but antagonized the effects of tunicamycin on ER stress markers. (iii) Tunicamycin and other known inducers of ER stress (hydrogen peroxide, doxorubicin, thapsigargin) induced cardiac myocyte death, and this was antagonized by guanabenz in a concentration-and time-dependent manner. (iv) ER stressors also induced acute or delayed contractile dysfunction in spontaneously beating EHTs and this was, with the notable exception of relaxation deficits under thapsigargin, not significantly affected by guanabenz. The data confirm that guanabenz interferes with ER stress-signalling and has protective effects on cell survival. Data show for the first time that this concept extends to cardiac myocytes. The modest protection in EHTs points to more complex mechanisms of force regulation in intact functional heart muscle."],["dc.description.sponsorship","European Union"],["dc.identifier.doi","10.1371/journal.pone.0098893"],["dc.identifier.isi","000336911400107"],["dc.identifier.pmid","24892553"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10495"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/33186"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Guanabenz Interferes with ER Stress and Exerts Protective Effects in Cardiac Myocytes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","899"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Journal of Biomolecular Screening"],["dc.bibliographiccitation.lastpage","909"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Sotoud, Hannieh"],["dc.contributor.author","Gribbon, Philip"],["dc.contributor.author","Ellinger, Bernhard"],["dc.contributor.author","Reinshagen, Jeanette"],["dc.contributor.author","Boknik, Peter"],["dc.contributor.author","Kattner, Lars"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Eschenhagen, Thomas"],["dc.date.accessioned","2018-11-07T09:20:58Z"],["dc.date.available","2018-11-07T09:20:58Z"],["dc.date.issued","2013"],["dc.description.abstract","Protein phosphatases (PP) are interesting drug targets. However, their ubiquitous presence and involvement in different, partially opposing signal pathways suggest that specificity may be achieved rather by targeting their interaction with subunits determining substrate specificity than the enzyme itself. An interesting subunit is phosphatase inhibitor-1 (I-1), which, in its protein kinase A-phosphorylated form (I-1(P)), inhibits the catalytic subunit of type 1 phosphatase (PP1c). In the current study, we established a colorimetric and a fluorescence-based assay system for the identification of compounds interfering with the inhibitory effect of I-1(P) on PP1c. The fluorescence assay exhibited 500-fold higher sensitivity toward PP1c. A nine-residue peptide containing the PP1c-binding motif (RVxF) of I-1 stimulated PP1c activity in the presence of I-1(P) (EC50 27 mu M and 2.3 mu M in the colorimetric and fluorescence assay, respectively). This suggests that the peptide interfered with the inhibitory effect of I-1(P) on PP1c and represents a proof-of-principle. The calculated Z factor for PP1c (0.84) and the PP1c-I-1(P) complex (0.73) confirmed the suitability of the fluorescence assay for high-throughput screenings (HTS). By testing several thousand small molecules, we suggest the advantages of kinetic measurements over single-point measurements using the fluorescence-based assay in an HTS format."],["dc.identifier.doi","10.1177/1087057113486000"],["dc.identifier.isi","000323115300005"],["dc.identifier.pmid","23606651"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13051"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29001"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/59"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["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.issn","1087-0571"],["dc.relation.issn","1552-454X"],["dc.relation.workinggroup","RG El-Armouche"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Development of a Colorimetric and a Fluorescence Phosphatase-Inhibitor Assay Suitable for Drug Discovery Approaches"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]