title: S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure.
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.
authors.affiliation: 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;
authors.forename: Konstantina
authors.initials: K
authors.lastname: Stathopoulou
authors.affiliation: 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;
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: 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;
authors.forename: Juliana
authors.initials: J
authors.lastname: Heidler
authors.affiliation: 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;
authors.forename: Angelika
authors.initials: A
authors.lastname: Piasecki
authors.affiliation: 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;
authors.forename: Florian
authors.initials: F
authors.lastname: Richter
authors.affiliation: 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;
authors.forename: Simon
authors.initials: S
authors.lastname: Diering
authors.affiliation: 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;
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.affiliation: Department of Clinical Chemistry/Central Laboratories, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Friedrich
authors.initials: F
authors.lastname: Buck
authors.affiliation: 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;
authors.forename: Sonia
authors.initials: S
authors.lastname: Donzelli
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, United Kingdom;
authors.forename: Ewald
authors.initials: E
authors.lastname: Schröder
authors.affiliation: 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;
authors.forename: Paul J M
authors.initials: PJ
authors.lastname: Wijnker
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany; and.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany; and.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: Department of Cell and Molecular Physiology, Loyola University, Chicago, Maywood, Illinois, USA.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sadayappan
authors.affiliation: 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;
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: 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;
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, United Kingdom;
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
authors.affiliation: 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.
authors.forename: Friederike
authors.initials: F
authors.lastname: Cuello
mesh_terms: D000328:Adult; D000818:Animals; D002317:Cardiovascular Agents / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010084:Oxidation-Reduction; D010766:Phosphorylation; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D002317:Cardiovascular Agents; D002352:Carrier Proteins; D005978:Glutathione; D000099163:Myosin Binding Protein C
keywords: cardiac disease; contractile function; cross-bridge cycling; post-translational modifications; redox proteomics
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