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Altered Cellular Protein Quality Control System Modulates Cardiomyocyte Function in Volume Overload-Induced Hypertrophy

ORCID
0000-0001-9793-3138
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Gömöri, Kamilla;
ORCID
0000-0003-3245-5504
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Herwig, Melissa;
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Hassoun, Roua;
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Budde, Heidi;
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Mostafi, Nusratul;
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Delalat, Simin;
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Modi, Suvasini;
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Begovic, Merima;
ORCID
0000-0001-8920-1666
Affiliation
Department of Pharmacology and Pharmacotherapy, University of Szeged, HU-6720 Szeged, Hungary
Szabados, Tamara;
Affiliation
Department of Pharmacology and Pharmacotherapy, University of Szeged, HU-6720 Szeged, Hungary
Pipis, Judit;
Affiliation
Department of Pharmacology and Pharmacotherapy, University of Szeged, HU-6720 Szeged, Hungary
Farkas-Morvay, Nikolett;
Affiliation
Department of Pharmacology and Pharmacotherapy, University of Szeged, HU-6720 Szeged, Hungary
Leprán, István;
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Kovács, Árpád;
Affiliation
Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, 44801 Bochum, Germany
Mügge, Andreas;
Affiliation
Pharmahungary Group, HU-6720 Szeged, Hungary
Ferdinandy, Péter;
Affiliation
Department of Pharmacology and Pharmacotherapy, University of Szeged, HU-6720 Szeged, Hungary
Görbe, Anikó;
ORCID
0000-0003-1936-6232
Affiliation
Department of Pharmacology and Pharmacotherapy, University of Szeged, HU-6720 Szeged, Hungary
Bencsik, Péter;
Affiliation
Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, 44801 Bochum, Germany
Hamdani, Nazha

Volume-induced hypertrophy is one of the risk factors for cardiac morbidity and mortality. In addition, mechanical and metabolic dysfunction, aging, and cellular redox balance are also contributing factors to the disease progression. In this study, we used volume overload (VO), which was induced by an aortocaval fistula in 2-month-old male Wistar rats, and sham-operated animals served as control. Functional parameters were measured by transthoracic echocardiography at termination 4- or 8-months after VO. The animals showed hypertrophic remodeling that was accompanied by mechanical dysfunction and increased cardiomyocyte stiffness. These alterations were reversible upon treatment with glutathione. Cardiomyocyte dysfunction was associated with elevated oxidative stress markers with unchanged inflammatory signaling pathways. In addition, we observed altered phosphorylation status of small heat shock proteins 27 and 70 and diminished protease expression caspases 3 compared to the matched control group, indicating an impaired protein quality control system. Such alterations might be attributed to the increased oxidative stress as anticipated from the enhanced titin oxidation, ubiquitination, and the elevation in oxidative stress markers. Our study showed an early pathological response to VO, which manifests in cardiomyocyte mechanical dysfunction and dysregulated signaling pathways associated with enhanced oxidative stress and an impaired protein quality control system.

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