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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Gerardo Alvarado
  • Viktória Jeney
  • Attila Tóth
  • Éva Csősz
  • Gergő Kalló
  • Thanh An Huynh
  • Csaba Hajnal
  • Judit Kalász
  • Enikő T Pásztor
  • István Édes
  • Magnus Gram
  • Bo Åkerström
  • Ann Smith
  • John W Eaton
  • György Balla
  • Zoltán Papp
  • József Balla
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
Originalspråkengelska
Sidor (från-till)248-262
TidskriftFree Radical Biology & Medicine
Volym89
Utgivningsnummersep 23
StatusPublished - 2015
PublikationskategoriForskning
Peer review utfördJa