Die Rolle von ERK1/2 im Prozess des kardialen Remodelings während chronischer Volumenbelastung
von Svenja Laura Jochmann
Datum der mündl. Prüfung:2023-12-07
Erschienen:2023-11-23
Betreuer:PD Dr. Dr. Moritz Thomas Schnelle
Gutachter:PD Dr. Dr. Moritz Thomas Schnelle
Gutachter:Prof. Dr. Dörthe Katschinski
Dateien
Name:Jochmann_Svenja_Dissertation_ediss.pdf
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Zusammenfassung
Englisch
Chronic heart failure is a disease of great socio-economic importance due to its high prevalence, reduced quality of life, poor prognosis and high healthcare costs. The causes of heart failure include hemodynamic stressors, which can be divided into volume load and pressure load. These stresses induce different types of cardiac remodeling with the development of different forms of hypertrophy - pressure overload leads to concentric hypertrophy, volume overload leads to eccentric hypertrophy. Due to the different remodeling processes, a thorough investigation of the signaling pathways is required to develop specific therapeutic approaches. As a typical MAP kinase (mitogen-activated protein kinase), ERK1/2 (extracellular signal-regulated kinases 1/2) plays a relevant role as a component of the signaling pathways of cardiac remodeling. To date, studies have mainly focused on the significance of ERK1/2 under pressure overload. In contrast, the role of ERK1/2 during volume overload in murine models in vivo has only been investigated to a limited extent. Our study aims to provide a more comprehensive understanding. A two-week volume overload was applied using the established model of an aorto-caval shunt in comparison to sham controls. The effects of volume overload were assessed using morphometric, echocardiographic, molecular genetic and histological parameters. In the first experimental setup, a wild-type study was performed in C57Bl/6N mice. As expected, two weeks of volume overload led to the development of eccentric hypertrophy and was accompanied by a significant reduction in phosphorylation of the ERK1/2-TEY motif (-28%). Thus, we were able to show for the first time that volume overload-induced eccentric hypertrophy is associated with reduced ERK1/2 activation in vivo. ERK1/2 appears to be required for the selectivity between concentric and eccentric hypertrophy. To our best knowledge, this is the first cardiac in vivo stress model that leads to a decrease in ERK1/2 activity and is therefore of great scientific interest. Based on these findings, we hypothesized that overexpression of ERK2 in cardiomyocytes influences cardiac remodeling with changes in volume overload-induced eccentric hypertrophy. In a second experimental setup, we conducted a comparative between cardiomyocyte-specific ERK2-overexpressing mice (ERK2tg) in the C57Bl/6J background and wild-type mice at basal level and after two weeks of volume overload. Cardiomyocyte-specific ERK2 overexpression did not alter basal cardiac phenotype and function or ERK1/2 activity. Surprisingly, ERK2 overexpression in cardiomyocytes in vivo at basal levels led to increased ANP expression at both mRNA and protein levels, a relationship that has not been shown previously. It appears that ERK2 modulates ANP expression irrespective of ERK1/2 activity or hypertrophy stimuli. Contrary to our hypothesis, there was no change in cardiac remodeling after two weeks of volume loading under ERK2 overexpression, demonstrated by echocardiographic, morphometric, molecular and histological studies. Further studies are needed to determine the exact role of ERK1/2 in cardiac remodeling induced by volume overload. A model with in vivo activation of ERK1/2 under volume overload, for example by specific phosphatase inactivation or MEK1/2 overexpression, would be of great interest. If such a model would show an adaptive modulation towards an improved compensation of volume overload, this could lead to interesting therapeutic approaches for the common illness chronic heart failure.
Keywords: volume overload; pressure overload; chronic heart failure; aorto-caval shunt; shunt; ERK 1/2; MAPK; transgenic mice