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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 and Édes, István, et al. (2015) In Free Radical Biology & Medicine 89(sep 23). p.248-262
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 (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... (More)
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. (Less)
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Free Radical Biology & Medicine
volume
89
issue
sep 23
pages
248 - 262
publisher
Elsevier
external identifiers
  • pmid:26409224
  • wos:000366355800024
  • scopus:84943183889
ISSN
0891-5849
DOI
10.1016/j.freeradbiomed.2015.07.158
language
English
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yes
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ab3d39e4-9ec6-4738-9bb3-38570a2678fd (old id 8034874)
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http://www.ncbi.nlm.nih.gov/pubmed/26409224?dopt=Abstract
date added to LUP
2015-10-03 13:45:38
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2017-05-21 03:14:38
@article{ab3d39e4-9ec6-4738-9bb3-38570a2678fd,
  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 (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.},
  author       = {Alvarado, Gerardo and Jeney, Viktória and Tóth, Attila and Csősz, Éva and Kalló, Gergő and An Huynh, Thanh and Hajnal, Csaba and Kalász, Judit and Pásztor, Enikő T and Édes, István and Gram, Magnus and Åkerström, Bo and Smith, Ann and Eaton, John W and Balla, György and Papp, Zoltán and Balla, József},
  issn         = {0891-5849},
  language     = {eng},
  number       = {sep 23},
  pages        = {248--262},
  publisher    = {Elsevier},
  series       = {Free Radical Biology & Medicine},
  title        = {Heme-induced contractile dysfunction in Human cardiomyocytes caused by oxidant damage to thick filament proteins.},
  url          = {http://dx.doi.org/10.1016/j.freeradbiomed.2015.07.158},
  volume       = {89},
  year         = {2015},
}