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Analyse des antifibrotischen Potenzials der betaadrenergen Signalkaskade und des PKA-Effektors Protein-Phosphatase-Inhibitor-1

dc.contributor.advisorEl-Armouche, Ali Prof. Dr.
dc.contributor.authorCevirgen, Ceyhun
dc.date.accessioned2017-05-17T08:47:09Z
dc.date.available2017-07-04T22:50:07Z
dc.date.issued2017-05-17
dc.identifier.urihttp://hdl.handle.net/11858/00-1735-0000-0023-3E46-4
dc.identifier.urihttp://dx.doi.org/10.53846/goediss-6299
dc.language.isodeude
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc610de
dc.titleAnalyse des antifibrotischen Potenzials der betaadrenergen Signalkaskade und des PKA-Effektors Protein-Phosphatase-Inhibitor-1de
dc.typedoctoralThesisde
dc.title.translatedAnalysis of the antifibrotic potential of the betadrenic pathway and the PKA effector Protein-Phosphatase-Inhibitor-1de
dc.contributor.refereeZeisberg, Elisabeth Prof. Dr.
dc.date.examination2017-06-27
dc.description.abstractengThe fibrotic remodeling of the heart appears in several cardiac diseases. Especially fibroblasts, which are known as the tissue producing cells in the heart, contribute to this process. Interacting with cardiomyocytes they play an important role for the cardiac functionality. Under pathological conditions fibroblasts differentiate to myofibroblasts, which are characterized by an increased production of extracellular matrix, secretion of profibrotic markers and the expression of smooth muscle actin (α-SMA). They play an important role in tissue fibrosis and hence they receive more and more attention in research. cAMP is associated with an inhibition of fibroblast transformation. Central aspects of this work are the β-adrenic receptor pathway and its potencial impact on fibrotic remodeling. In contrast to cardiomyocytes PKA-dependend phosphorylation in fibroblasts is mainly mediated by the β2-receptor subtype. The β1-receptor does not seem to be involved in this mechanism. In this work the effects of chronic β2-receptor stimulation on the expression of profibrotic markers in cultured fibroblasts from neonatal rat heart were closer analysed. This set-up was meant to simulate the conditions in chronic heart failure, when catecholamine levels reach a maximum. Through this intervention the expression of the fibrosis associated secretory marker CTGF was significantly reduced, whereas α-SMA levels remained constant. Considering the constant α-SMA levels a reconversion to fibroblasts did not take place. The downregulation of CTGF is a result of increasing cAMP-levels induced by β-ad¬renic stimulation. It is known, that the second messenger cAMP has antifibrotic potential. In cAMP-assays we could demonstrate an increase of cAMP-levels after application of isoprenaline. A side effect of the chronic stimulation is the phenomenon of β-adrenic desensitization, which could be seen in the phosphorylation of CREB and the decreasing cAMP-levels. Another question, which resulted from the findings, was whether a boost of the β-adrenic pathway induces an additional antifibrotic effect. For this purpose inhibitor-1 (I-1), a well known amplifier of the pathway, was used by infecting fibroblasts with Ad-I-1. By overexpressing I-1 an increase of PKA-dependend phosphorylation level was achieved. Nevertheless there was no hint of an additional profibrotic effect in presence of I-1.de
dc.contributor.coRefereeOppermann, Martin Prof. Dr.
dc.subject.gerFibroblastende
dc.subject.engfibroblastsde
dc.identifier.urnurn:nbn:de:gbv:7-11858/00-1735-0000-0023-3E46-4-6
dc.affiliation.instituteMedizinische Fakultätde
dc.subject.gokfullPharmakologie / Toxikologie / Pharmakotherapie - Allgemein- und Gesamtdarstellungen (PPN61987550X)de
dc.description.embargoed2017-07-04
dc.identifier.ppn88765844X


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