Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02087-y
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Protein kinase D plays a crucial role in cardiac homeostasis by regulating protein phosphorylation and oxidation
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M. Begovic1, M. Herwig2, R. Hassoun3, H. Budde4, A. Mügge5, J. Fielitz6, N. Hamdani7
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1Molekulare und Experimentelle Kardiologie, Institut für Forschung und Lehre/ St. Josephs, Bochum; 2Molekulare und Experimentelle Kardiologie, Institut für Forschung und Lehre (IFL), St. Josef Hospital, Ruhr-Universität Bochum, Bochum; 3Molecular and Experimental Cardiology, Institut für Forschung und Lehre (IFL), Ruhr University Bochum, Bochum; 4Molekulare und Experimentelle Kardiologie, Ruhr-Universität Bochum, Bochum; 5Medizinische Klinik II, Kardiologie, Klinikum der Ruhr-Universität Bochum, Bochum; 6Klinik und Poliklinik für Innere Medizin B, Universitätsmedizin Greifswald, Greifswald; 7Forschungslabor Molekulare Kardiologie, Kath. Klinikum Bochum, Bochum;
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Background:
Protein kinase D (PKD) enzymes play crucial roles in regulating myocardial contraction, hypertrophy and remodelling. PKD phosphorylates myofilament proteins and the giant protein titin is one of its substrates. Here, we aimed to investigate the effects of PKD on cardiomyocyte function based on protein oxidation.
Results:
In this study, we used cardiomyocyte-specific PKD knock-out mice (PKD cKO) and its corresponding wild type. The model was characterized by cardiomyocyte dysfunction. We found increased passive stiffness of isolated permeabilized cardiomyocytes in the KO mice, which was associated with increased titin oxidation, but unchanged titin ubiquitination. Myofilament calcium sensitivity (pCa50) was increased and maximum Ca2+-activated tension was reduced in KO mice. These alterations were associated with increased oxidation of the small myofilament proteins myosin binding protein C and troponin I, in addition to a phosphorylation deficit of both proteins at different phospho-sites. Increased passive stiffness and pCa50 and reduced maximum Ca2+-activated tension were reversed upon treatment of isolated permeabilized cardiomyocytes with reduced glutathione (GSH), indicating the contribution of myofilament protein oxidation to cardiomyocyte dysfunction. The KO mice indeed showed increased oxidative stress and inflammation. Both contributed to the activation of autophagy and heat shock response via the inhibition of the mammalian target of rapamycin (mTOR) in the KO mice. This plays an important role in stress response, which also contributes to cardiomyocyte dysfunction as the treatment with heart shock proteins reversed cardiomyocyte dysfunction in KO mice and corrected it to values observed in wild type.
Conclusion:
These findings establish a previously unknown role for PKD in regulating diastolic passive properties, myofilament calcium sensitivity, and maximum Ca2+-activated tension and emphasizing the importance of PKD in maintaining oxidative stress and inflammation balance and cardiomyocyte function.
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https://dgk.org/kongress_programme/ht2022/aBS675.html
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