Kardiale Phänotypisierung einer transgenen Mauslinie mit herzspezifischer Calcium-Calmodulin-Kinase IIδc- Überexpression auf einem Phosphatase-Inhibitor-1- Knockout-Hintergrund

Cardiac phenotyping of a transgenic mouse model with cardiac specific Ca2+/calmodulin-dependent protein kinase IIδc overexpression on a phosphatase inhibitor -1 knockout background

von Christina Andrea Anna Brammen
Dissertation
Datum der mündl. Prüfung:2015-09-29
Erschienen:2015-09-29
Betreuer:Prof. Dr. Ali El-Armouche
Gutachter:Prof. Dr. Stephan E. Lehnert
Gutachter:Prof. Dr. Martin Oppermann
Zum Verlinken/Zitieren: http://dx.doi.org/10.53846/goediss-5286

 

 

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Englisch

Since years cardiovascular diseases are the leading cause of death in our population. In particular heart failure is of considerable importance. So, to understand molecular alterations in signal transduction and to identify new therapeutic targets is even more important. At the cellular level, the β - adrenergic desensitization plays a central role. It leads to altered expressionlevels and phosphorylation of proteins which plays a crucial role in Ca2+ homeostasis and excitation-contraction coupling. I-1 acts as a distal amplifier element of the β-adrenergic cascade. PKA-dependent phosphorylated and activated, I-1 selectively inhibits the cardiac dominant PP1 and increases the phosphorylation of various proteins. Ultimately, I-1 leads to an increased β-adrenergic sensitivity. In heart failure I-1 is downregulated, and formulated provocative, we can speak of an "intracellular β-blocker". The aim of this work was to analyze the antiarrhythmic phenotype of I-1 KO mice at the cellular level, which was already shown in vivo. At the same time the cardiac effects of an I-1 ablation should be examined in transgenic CaMKIIδc-mice. So far, an indirect crosstalk between the CaMKIIδc and I-1 is assumed on the RyR2, since both proteins attach to the CaMKIIδc Ser2815 phosphorylation site with opposite effects. The hypothesis is that an I-1 depended reduction of the SR Ca2+ leak since birth can improve the severe CaMKIIδc associated phenotype. To verify this hypothesis, the Ca2+ homeostasis and the SR Ca2+-leak was investigated. It was found that the diastolic Ca2+-level was significantly reduced by I-1 ablation. This is in line with a significantly reduced Ca2+-leak and a reduced incidence of SCaEs. Once again these results suggest that the antiarrhythmic phenotype of I-1 KO mice could improve the severe CaMKIIδc-associated phenotype by reducing the SR Ca2+-leak in CaMKIIδc x I-1 KO cardiomyocytes.  Surprisingly, and contrary to my hypothesis an ablation of I-1 in transgenic CaMKIIδc mice did not improved survival, but rather led to an increase in cardiac hypertrophy and contractile dysfunction. The excitation-contraction coupling was not significantly affected and showed no significant differences compared to CaMKIIδc transgenic mice without I-1 ablation. In particular, the SR Ca2+-leak was not reduced.  Until now, it is mechanistically unclear why there was this unexpected deterioration of the phenotype. Nevertheless, inhibition of I-1 remains a potential therapeutic target especially with respect to the shown reduced SR Ca2+-leak and the antiarrhythmic phenotype in I-1 KO mice.
Keywords: phosphatase inhibitor -1 knockout; Ca2+/calmodulin-dependent protein kinase IIδc; β - adrenergic desensitization; SR Ca2+ leak
Schlagwörter: Phosphatase-Inhibitor-1- Knockout; Calcium-Calmodulin-Kinase IIδc; β - adrenerge Desensitivierung; SR-Ca2+-Leck
 
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