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

Gerardo Alvarado, Viktória Jeney, Attila Tóth, Éva Csosz, Gergo Kalló, An T. Huynh, Csaba Hajnal, Judit Kalász, Eniko T. Pásztor, István Édes, Magnus Gram, Bo Akerström, Ann Smith, John W. Eaton, György Balla, Zoltán Papp, József Balla

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 Ca2+-sensitivity (pCa50) were monitored in permeabilized human ventricular cardiomyocytes. Heme exposure altered cardiomyocyte morphology and evoked robust decreases in Ca2+-activated maximal active force (Fo) while increasing Ca2+-independent passive force (Fpassive). Heme treatments, either alone or in combination with H2O2, did not affect pCa50. The increase in Fpassive 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.

Original languageEnglish
Article number12546
Pages (from-to)248-262
Number of pages15
JournalFree Radical Biology and Medicine
Volume89
DOIs
Publication statusPublished - Dec 1 2015

Keywords

  • Calcium sensitivity
  • Cardiac myosin binding protein C
  • Cardiomyocyte
  • Contractile function
  • HO
  • Heme
  • Myosin heavy chain
  • Myosin light chain 1
  • Oxidation
  • Sulfenic acid
  • Titin

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Heme-induced contractile dysfunction in Human cardiomyocytes caused by oxidant damage to thick filament proteins'. Together they form a unique fingerprint.

  • Cite this

    Alvarado, G., Jeney, V., Tóth, A., Csosz, É., Kalló, G., Huynh, A. T., Hajnal, C., Kalász, J., Pásztor, E. T., Édes, I., Gram, M., Akerström, B., Smith, A., Eaton, J. W., 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 and Medicine, 89, 248-262. [12546]. https://doi.org/10.1016/j.freeradbiomed.2015.07.158