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dc.contributor.advisor Streckfuß-Bömeke, Katrin PD Dr.
dc.contributor.author Guessoum, Celina Isabelle
dc.date.accessioned 2020-04-06T08:54:17Z
dc.date.available 2020-08-24T22:50:03Z
dc.date.issued 2020-04-06
dc.identifier.uri http://hdl.handle.net/21.11130/00-1735-0000-0005-1377-0
dc.language.iso eng de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 610 de
dc.title Analysis of catecholamine-induced beta-adrenergic signaling in TTS by patient-specific pluripotent stem cell-derived cardiomyocytes de
dc.type doctoralThesis de
dc.contributor.referee Zelarayan-Behrend, Laura PD Dr.
dc.date.examination 2020-04-21
dc.description.abstracteng Takotsubo syndrome (TTS) is a heart disease characterized by left ventricular dysfunction. Its clinical presentation frequently mimics acute myocardial infarction and the disease mainly occurs in postmenopausal women after exposure to emotional or physical stress. High catecholamine concentrations have been suggested as the primary cause of TTS. Since a genetic predisposition is presumed to be very likely, the  A first breakthrough in understanding the still unknown pathomechanism of TTS was the work published by Wittstein and his colleagues in 2005, that suggested high catecholamine concentrations as the primary cause of TTS. Several other hypotheses have been suggested ever since and a genetic predisposition is presumed to be very likely. Therefore, the demand for a patient-specific disease model to further study the pathophysiology of TTS is high. The aims of this thesis were to explore whether human induced pluripotent stem cells (hiPSCs) of TTS patients can serve as a patient-specific disease model to further study the TTS pathophysiology and to establish catecholamine-dependent stress conditions in hiPSC-cardiomyocytes (hiPSC-CMs) derived from TTS patients. Furthermore, TTS-specific stress markers and the phosphorylation status of protein kinase A targets after beta-adrenergic stimulation were analyzed. The generated hiPSCs of TTS patient 1 used in this study were characterized to proof their pluripotency. All analyzed lines maintained full pluripotency, genomic integrity, and in vitro and in vivo differentiation capacity. The hiPSCs from TTS and controls were able to differentiate into functional, beating cardiomyocytes (hiPSC-CMs) with cardiac marker expression and regular sarcomeric structure. These cardiomyocytes were then treated with different catecholamines (epinephrine (Epi), isoprenaline (Iso), phenylephrine (Pe)) of varying concentrations for 2 and 20 hours to analyze the expression of potential cardiac stress markers on mRNA level. While NPPA and NPPB expression significantly increased after catecholamine treatment, NR4A1 showed the most impressive upregulation. The latter was also significantly higher expressed in hiPSC-CMs of TTS patients than in those of healthy controls after treatment with high Iso (5 mmol/L). Catecholamine treatment for 2 hours showed a more effective stress induction than catecholamine treatment for 20 hours. To further elucidate the beta adrenergic signaling pathway, we analyzed phosphorylation of protein kinase A targets after treatment with Epi and Iso. High Epi (500 µmol/L) and high Iso (5 mmol/L) concentrations resulted in significantly higher phosphorylation of ryanodine receptor 2 (RYR2) at Serine 2808 in TTS-hiPSC-CMs compared to control-hiPSC-CMs. Extracellular-signal regulated kinase (ERK) showed maximum phosphorylation after treatment with 100 nmol/L Epi or Iso respectively. Hexosamine biosynthesis pathway enzymes (OGT, GFAT1) – as a possible target of NR4A1 – were also analyzed, but showed no significant changes after catecholamine treatment. Overall, the work of this thesis showed, that hiPSC-CMs present a suitable patient-specific disease model to further study the pathophysiology of TTS and that hiPSC-CMs of TTS patients differ significantly in their catecholamine susceptibility from the hiPSC-CMs of healthy controls.  de
dc.contributor.coReferee Oppermann, Martin Prof. Dr.
dc.subject.eng TTS pathogenesis de
dc.subject.eng broken heart syndrome de
dc.subject.eng catecholamine de
dc.subject.eng iPSC cardiomyocytes de
dc.identifier.urn urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-1377-0-5
dc.affiliation.institute Medizinische Fakultät de
dc.subject.gokfull Kardiologie (PPN619875755) de
dc.subject.gokfull Pathophysiologie {Medizin} (PPN619875305) de
dc.description.embargoed 2020-08-24
dc.identifier.ppn 1694150461
dc.date.ppexamination 2020-06-09

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