Die Rolle der Serin/Threonin-Phosphatasen bei der Dysregulation des Calcium-Stoffwechsels in der menschlichen Herzerkrankung

Eiringhaus, Jörg

dc.contributor.advisor	Kroemer, Heyo K. Prof. Dr.
dc.contributor.author	Eiringhaus, Jörg
dc.date.accessioned	2019-01-04T11:29:24Z
dc.date.available	2019-01-23T23:50:04Z
dc.date.issued	2019-01-04
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-002E-E54B-4
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-7210
dc.language.iso	deu	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	610	de
dc.title	Die Rolle der Serin/Threonin-Phosphatasen bei der Dysregulation des Calcium-Stoffwechsels in der menschlichen Herzerkrankung	de
dc.type	doctoralThesis	de
dc.title.translated	The role of serine/threonine phosphatases in cardiac calcium homeostasis in the development of human heart failure	de
dc.contributor.referee	Sossalla, Samuel T. Prof. Dr.
dc.date.examination	2019-01-16
dc.description.abstracteng	Disruption of Ca2+-homeostasis is a key pathomechanism in the development of heart failure by compromising EC-coupling. While the role of respective kinases has been extensively studied during the last decades, the contribution of conversely acting serine/threonine phosphatases to arrhythmias in structural heart disease remains unknown. This study investigates for the first time the functional influence of cardiac phosphatases in the development of human heart failure and arrhythmias. Human ventricular myocardium of patients with cardiac hypertrophy with preserved ejection fraction and patients with end stage heart failure was implemented in this thesis. In cardiac hypertrophy an inhibition of PP1 and PP2A using Okadaic Acid resulted in an increased SR-Ca2+-leak. Conclusively, the frequency of cellular arrhythmic events was also increased, as was the amplitude of systolic Ca2+-transients and the SR-Ca2+-load. In heart failure, phosphatase inhibition further increased the SR-Ca2+-leak and the frequency of cellular arrhythmic events. The amplitude of systolic Ca2+-transients was increased by inhibition of PP1 and PP2A, whereas the SR-Ca2+-load was not changed. Importantly, a selective activation of PP1 by the novel phosphatase disrupting peptide PDP3 yielded a prominent reduction of the SR-Ca2+-leak and reduced the frequency of cellular arrhythmic events in human end stage failing cardiomyocytes. In this context no negative inotropic effects could be detected. In summary, this study is the first to functionally investigate the role of phosphatases for Ca2+-homeostasis in diseased human myocardium. The data indicate that modulations of phosphatase activity potently impact Ca2+-homeostasis. Whereas an inhibition of PP1 and PP2A leads to an increase of cellular arrhythmias, an activation of PP1 potently counteracts an increased kinase activity in heart failure and seals the arrhythmogenic SR-Ca2+-leak.	de
dc.contributor.coReferee	Voigt, Niels Prof. Dr.
dc.contributor.thirdReferee	Schön, Margarete Prof. Dr.
dc.subject.ger	Herzinsuffizienz	de
dc.subject.ger	Arrhythmien	de
dc.subject.ger	SR-Calcium-Leck	de
dc.subject.ger	Proteinkinasen	de
dc.subject.ger	Proteinphosphatasen	de
dc.subject.ger	PKA	de
dc.subject.ger	CaMKII	de
dc.subject.ger	PP1	de
dc.subject.ger	PP2A	de
dc.subject.ger	PDP3	de
dc.subject.eng	heart failure	de
dc.subject.eng	arrhythmias	de
dc.subject.eng	SR calcium leak	de
dc.subject.eng	protein kinases	de
dc.subject.eng	protein phosphatases	de
dc.subject.eng	PKA	de
dc.subject.eng	CaMKII	de
dc.subject.eng	PP1	de
dc.subject.eng	PP2A	de
dc.subject.eng	PDP3	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E54B-4-7
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	Kardiologie (PPN619875755)	de
dc.description.embargoed	2019-01-23
dc.identifier.ppn	1045680990

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