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

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Heme-induced contractile dysfunction in Human cardiomyocytes caused by oxidant damage to thick filament proteins. / Alvarado, Gerardo; Jeney, Viktória; Tóth, Attila; Csősz, Éva; Kalló, Gergő; An Huynh, Thanh; Hajnal, Csaba; Kalász, Judit; Pásztor, Enikő T; Édes, István; Gram, Magnus; Åkerström, Bo; Smith, Ann; Eaton, John W; Balla, György; Papp, Zoltán; Balla, József.

In: Free Radical Biology & Medicine, Vol. 89, No. sep 23, 2015, p. 248-262.

Research output: Contribution to journalArticle

Harvard

Alvarado, G, Jeney, V, Tóth, A, Csősz, É, Kalló, G, An Huynh, T, Hajnal, C, Kalász, J, Pásztor, ET, Édes, I, Gram, M, Åkerström, B, Smith, A, Eaton, JW, Balla, G, Papp, Z & Balla, J 2015, 'Heme-induced contractile dysfunction in Human cardiomyocytes caused by oxidant damage to thick filament proteins.', Free Radical Biology & Medicine, vol. 89, no. sep 23, pp. 248-262. https://doi.org/10.1016/j.freeradbiomed.2015.07.158

APA

CBE

Alvarado G, Jeney V, Tóth A, Csősz É, Kalló G, An Huynh T, Hajnal C, Kalász J, Pásztor ET, Édes I, Gram M, Åkerström B, Smith A, Eaton JW, Balla G, Papp Z, Balla J. 2015. Heme-induced contractile dysfunction in Human cardiomyocytes caused by oxidant damage to thick filament proteins. Free Radical Biology & Medicine. 89(sep 23):248-262. https://doi.org/10.1016/j.freeradbiomed.2015.07.158

MLA

Vancouver

Author

Alvarado, Gerardo ; Jeney, Viktória ; Tóth, Attila ; Csősz, Éva ; Kalló, Gergő ; An Huynh, Thanh ; Hajnal, Csaba ; Kalász, Judit ; Pásztor, Enikő T ; Édes, István ; Gram, Magnus ; Åkerström, Bo ; Smith, Ann ; Eaton, John W ; Balla, György ; Papp, Zoltán ; Balla, József. / Heme-induced contractile dysfunction in Human cardiomyocytes caused by oxidant damage to thick filament proteins. In: Free Radical Biology & Medicine. 2015 ; Vol. 89, No. sep 23. pp. 248-262.

RIS

TY - JOUR

T1 - Heme-induced contractile dysfunction in Human cardiomyocytes caused by oxidant damage to thick filament proteins.

AU - Alvarado, Gerardo

AU - Jeney, Viktória

AU - Tóth, Attila

AU - Csősz, Éva

AU - Kalló, Gergő

AU - An Huynh, Thanh

AU - Hajnal, Csaba

AU - Kalász, Judit

AU - Pásztor, Enikő T

AU - Édes, István

AU - Gram, Magnus

AU - Åkerström, Bo

AU - Smith, Ann

AU - Eaton, John W

AU - Balla, György

AU - Papp, Zoltán

AU - Balla, József

PY - 2015

Y1 - 2015

N2 - 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 (Fpassive). Heme treatments, either alone or in combination with H2O2, did not affect pCa50. The increase in Fpassive started at 3µM 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 140kDa 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.

AB - 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 (Fpassive). Heme treatments, either alone or in combination with H2O2, did not affect pCa50. The increase in Fpassive started at 3µM 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 140kDa 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.

U2 - 10.1016/j.freeradbiomed.2015.07.158

DO - 10.1016/j.freeradbiomed.2015.07.158

M3 - Article

VL - 89

SP - 248

EP - 262

JO - Free Radical Biology & Medicine

T2 - Free Radical Biology & Medicine

JF - Free Radical Biology & Medicine

SN - 0891-5849

IS - sep 23

ER -