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Free Radic Biol Med. 2015 Dec;89:248-62. doi: 10.1016/j.freeradbiomed.2015.07.158. Epub 2015 Sep 25.

Heme-induced contractile dysfunction in human cardiomyocytes caused by oxidant damage to thick filament proteins.

Author information

1
Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; Department of Nephrology, Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
2
Department of Nephrology, Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences, H-4032 Debrecen, Hungary.
3
Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
4
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
5
Department of Clinical Sciences, Division of Infection Medicine, Lund University, Lund, Sweden.
6
School of Biological Sciences, University of Missouri-Kansas City, MO, USA.
7
Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40059, USA.
8
MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences, H-4032 Debrecen, Hungary; Institute of Pediatrics, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
9
Department of Nephrology, Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences, H-4032 Debrecen, Hungary. Electronic address: balla@internal.med.unideb.hu.

Abstract

Intracellular free heme predisposes to oxidant-mediated tissue damage. We hypothesized that free heme causes alterations in myocardial contractility via disturbed structure and/or regulation of the contractile proteins. Isometric force production and its Ca(2+)-sensitivity (pCa50) were monitored in permeabilized human ventricular cardiomyocytes. Heme exposure altered cardiomyocyte morphology and evoked robust decreases in Ca(2+)-activated maximal active force (Fo) while increasing Ca(2+)-independent passive force (F passive). Heme treatments, either alone or in combination with H2O2, did not affect pCa50. The increase in F passive started at 3 µM heme exposure and could be partially reversed by the antioxidant dithiothreitol. Protein sulfhydryl (SH) groups of thick myofilament content decreased and sulfenic acid formation increased after treatment with heme. Partial restoration in the SH group content was observed in a protein running at 140 kDa after treatment with dithiothreitol, but not in other proteins, such as filamin C, myosin heavy chain, cardiac myosin binding protein C, and α-actinin. Importantly, binding of heme to hemopexin or alpha-1-microglobulin prevented its effects on cardiomyocyte contractility, suggesting an allosteric effect. In line with this, free heme directly bound to myosin light chain 1 in human cardiomyocytes. Our observations suggest that free heme modifies cardiac contractile proteins via posttranslational protein modifications and via binding to myosin light chain 1, leading to severe contractile dysfunction. This may contribute to systolic and diastolic cardiac dysfunctions in hemolytic diseases, heart failure, and myocardial ischemia-reperfusion injury.

KEYWORDS:

Calcium sensitivity; Cardiac myosin binding protein C; Cardiomyocyte; Contractile function; H(2)O(2); Heme; Myosin heavy chain; Myosin light chain 1; Oxidation; Sulfenic acid; Titin

[Indexed for MEDLINE]

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