Expression und Phosphorylierung von Proteinen der Calciumhomöostase im Vorhof- und Ventrikelmyokard von Mäusen mit kardialer JDP2-Überexpression
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Philipps-Universität Marburg
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Heart failure and arrhythmias, such as atrial fibrillation, are life-threatening and widespread conditions with increasing prevalence due to the rise in average life expectancy brought about by improvements and expansions in therapeutic options. They are associated with a significant reduction in quality of life. The molecular mechanisms underlying these conditions are crucial for understanding and ultimately identifying therapeutic targets. Calcium-regulating proteins play a key role in myocardial function and are altered in many models studying heart failure and arrhythmias. Medication therapies targeting calcium-regulating proteins have become widely established.
The transcription factor Jun Dimerization Protein 2 (JDP2) has been identified as a prognostic marker for the development of heart failure in patients after suffering a myocardial infarction. Further studies showed cardiac changes caused by under- or overexpression of this protein. In the mouse model studied here, the overexpression of JDP2 for five weeks led to massive, biatrial dilation, heart failure, and paroxysmal atrial fibrillation. To figure out whether changes in calcium homeostasis may have contributed to the development of heart failure and atrial fibrillation, the expression and phosphorylation of key calcium-regulating proteins in atrial and ventricular myocardium were assessed using the Westen Blot method. The following proteins were examined: CaV1.2, Calsequestrin, SERCA2a, RyR2, and the gap junction protein Connexin40. Through the CaV1.2 calcium channel, calcium enters the myocardial cell during the action potential, thereby triggering the cascade of electro-mechanical coupling. Although expression of this channel in the atrium was reduced, this change was not statistically significant. In the ventricular myocardium, expression was significantly reduced by about 60%. Calsequestrin is a calcium-binding protein that provides calcium for release into the cytosol during electro-mechanical coupling in the sarcoplasmic reticulum (SR). No significant changes were detected in either the atrium or the ventricle. SERCA2a is a calcium-ATPase that pumps calcium from the cytosol into the SR. It has long been a potential therapeutic target in research. Both atrial and ventricular myocardium showed a significant reduction in SERCA2a expression by about 40%. The Ryanodine Receptor Type 2 (RyR2) and its phosphorylation sites (Ser-2808 and Ser-2814) were also investigated. This channel is responsible for calcium release from the SR into the cytosol. While the expression in the atrial myocardium was reduced, this change was not statistically significant, but a significant reduction of about 50% was observed in the ventricular myocardium. For the phosphorylation sites, hypophosphorylation of Ser-2808 by approximately 60% was detected in the atrium. In the ventricular myocardium, Ser-2814 was notably hyperphosphorylated (about 90%). The expression of Connexin40, an essential protein for action potential conduction through gap junctions, was significantly reduced. A reduction of about 70% was observed in the atrium and about 40% in the ventricular myocardium.
The reduction in expression of CaV1.2, SERCA2a, and RyR2 in the ventricle may have led to a reduced calcium transient and likely contributed to heart failure. The observed arrhythmic tendency in the JDP2 mice may, at least partially, be caused by the reduced expression of Connexin40 in the atrium. In the atrium, the reduced expression of SERCA2a and the hypophosphorylation of Ser-2809 (RyR2) could have led to a diminished calcium transient, thereby limiting contractility. Both atrial and ventricular myocardium in the JDP2 mice exhibited remodeling of the calcium-regulating proteins, though this remodeling differed between the atrium and the ventricle. The overexpression of JDP2 led to paroxysmal atrial fibrillation and heart failure. The changes in calcium-regulating proteins and phosphorylation status during remodeling contribute to these changes and thus provide potential new therapeutic targets for the treatment of paroxysmal atrial fibrillation and heart failure.
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Created: 2025Issued: 2025-09-15Updated: 2025-09-15
Faculty
Medizin
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Philipps-Universität Marburg
Language
ger
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DoctoralThesis
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cardiac remodellingcalcium homeostasisJDP2overexpression
DDC-Numbers
610
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Scherer, Anna Ulrike: Expression und Phosphorylierung von Proteinen der Calciumhomöostase im Vorhof- und Ventrikelmyokard von Mäusen mit kardialer JDP2-Überexpression. : Philipps-Universität Marburg 2025-09-15. DOI: https://doi.org/10.17192/z2025.0433.
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This item has been published with the following license: In Copyright