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FASEB J. 2016 May;30(5):1849-64. doi: 10.1096/fj.201500048. Epub 2016 Feb 2.

S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure.

Author information

1
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Frankfurt, Germany;
2
Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany; Cluster of Excellence "Macromolecular Complexes," Goethe University, Frankfurt am Main, Germany; Partner Site Rhein/Main, Frankfurt, Germany;
3
Department of Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center Amsterdam, Amsterdam, The Netherlands; ICIN-The Netherlands Heart Institute, Utrecht, The Netherlands;
4
Department of Clinical Chemistry/Central Laboratories, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
5
King's British Heart Foundation Centre, King's College London, London, United Kingdom;
6
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Frankfurt, Germany; Department of Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center Amsterdam, Amsterdam, The Netherlands;
7
Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany; and.
8
Department of Cell and Molecular Physiology, Loyola University, Chicago, Maywood, Illinois, USA.
9
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Frankfurt, Germany; f.cuello@uke.de.

Abstract

Cardiac myosin-binding protein C (cMyBP-C) regulates actin-myosin interaction and thereby cardiac myocyte contraction and relaxation. This physiologic function is regulated by cMyBP-C phosphorylation. In our study, reduced site-specific cMyBP-C phosphorylation coincided with increased S-glutathiolation in ventricular tissue from patients with dilated or ischemic cardiomyopathy compared to nonfailing donors. We used redox proteomics, to identify constitutive and disease-specific S-glutathiolation sites in cMyBP-C in donor and patient samples, respectively. Among those, a cysteine cluster in the vicinity of the regulatory phosphorylation sites within the myosin S2 interaction domain C1-M-C2 was identified and showed enhanced S-glutathiolation in patients. In vitro S-glutathiolation of recombinant cMyBP-C C1-M-C2 occurred predominantly at Cys(249), which attenuated phosphorylation by protein kinases. Exposure to glutathione disulfide induced cMyBP-C S-glutathiolation, which functionally decelerated the kinetics of Ca(2+)-activated force development in ventricular myocytes from wild-type, but not those from Mybpc3-targeted knockout mice. These oxidation events abrogate protein kinase-mediated phosphorylation of cMyBP-C and therefore potentially contribute to the reduction of its phosphorylation and the contractile dysfunction observed in human heart failure.-Stathopoulou, K., Wittig, I., Heidler, J., Piasecki, A., Richter, F., Diering, S., van der Velden, J., Buck, F., Donzelli, S., Schröder, E., Wijnker, P. J. M., Voigt, N., Dobrev, D., Sadayappan, S., Eschenhagen, T., Carrier, L., Eaton, P., Cuello, F. S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure.

KEYWORDS:

cardiac disease; contractile function; cross-bridge cycling; post-translational modifications; redox proteomics

PMID:
26839380
PMCID:
PMC4836368
DOI:
10.1096/fj.201500048
[Indexed for MEDLINE]
Free PMC Article

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