title: Myeloperoxidase impairs the contractile function in isolated human cardiomyocytes.
abstract: We set out to characterize the mechanical effects of myeloperoxidase (MPO) in isolated left-ventricular human cardiomyocytes. Oxidative myofilament protein modifications (sulfhydryl (SH)-group oxidation and carbonylation) induced by the peroxidase and chlorinating activities of MPO were additionally identified. The specificity of the MPO-evoked functional alterations was tested with an MPO inhibitor (MPO-I) and the antioxidant amino acid Met. The combined application of MPO and its substrate, hydrogen peroxide (H2O2), largely reduced the active force (Factive), increased the passive force (Fpassive), and decreased the Ca(2+) sensitivity of force production (pCa50) in permeabilized cardiomyocytes. H2O2 alone had significantly smaller effects on Factive and Fpassive and did not alter pCa50. The MPO-I blocked both the peroxidase and the chlorinating activities, whereas Met selectively inhibited the chlorinating activity of MPO. All of the MPO-induced functional effects could be prevented by the MPO-I and Met. Both H2O2 alone and MPO + H2O2 reduced the SH content of actin and increased the carbonylation of actin and myosin-binding protein C to the same extent. Neither the SH oxidation nor the carbonylation of the giant sarcomeric protein titin was affected by these treatments. MPO activation induces a cardiomyocyte dysfunction by affecting Ca(2+)-regulated active and Ca(2+)-independent passive force production and myofilament Ca(2+) sensitivity, independent of protein SH oxidation and carbonylation. The MPO-induced deleterious functional alterations can be prevented by the MPO-I and Met. Inhibition of MPO may be a promising therapeutic target to limit myocardial contractile dysfunction during inflammation.
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Kalász
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
authors.forename: Enikő T
authors.initials: ET
authors.lastname: Pásztor
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Fagyas
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Balogh
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Tóth
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
authors.forename: Viktória
authors.initials: V
authors.lastname: Csató
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Édes
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Papp
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary. Electronic address: borbelya@med.unideb.hu.
authors.forename: Attila
authors.initials: A
authors.lastname: Borbély
mesh_terms: D000328:Adult; D020013:Calcium Signaling; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000201:enzymology*; D009195:Peroxidase / Q000502:physiology*
chemical_list: D009195:Peroxidase
keywords: Antioxidants; Cardiomyocyte contractile function; Free radicals; Hydrogen peroxide; Myeloperoxidase; Oxidative posttranslational protein modifications