Peroxynitrite induces HMGB1 release by cardiac cells in vitro and HMGB1 upregulation in the infarcted myocardium in vivo.

High-mobility group box 1 (HMGB1) is a nuclear protein actively secreted by immune cells and passively released by necrotic cells that initiates pro-inflammatory signalling through binding to the receptor for advance glycation end-products. HMGB1 has been established as a key inflammatory mediator during myocardial infarction, but the proximal mechanisms responsible for myocardial HMGB1 expression and release in this setting remain unclear. Here, we investigated the possible involvement of peroxynitrite, a potent cytotoxic oxidant formed during myocardial infarction, on these processes.
The ability of peroxynitrite to induce necrosis and HMGB1 release in vitro was evaluated in H9c2 cardiomyoblasts and in primary murine cardiac cells (myocytes and non-myocytes). In vivo, myocardial HMGB1 expression and nitrotyrosine content (a marker of peroxynitrite generation) were determined following myocardial ischaemia and reperfusion in rats, whereas peroxynitrite formation was inhibited by two different peroxynitrite decomposition catalysts: 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (III) (FeTPPS) or Mn(III)-tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP). In all types of cells studied, peroxynitrite (100 μM) elicited significant necrosis, the loss of intracellular HMGB1, and its passive release into the medium. In vivo, myocardial ischaemia-reperfusion induced significant myocardial necrosis, cardiac nitrotyrosine formation, and marked overexpression of myocardial HMGB1. FeTPPS reduced nitrotyrosine, decreased infarct size, and suppressed HMGB1 overexpression, an effect that was similarly obtained with MnTBAP.
These findings indicate that peroxynitrite represents a key mediator of HMGB1 overexpression and release by cardiac cells and provide a novel mechanism linking myocardial oxidative/nitrosative stress with post-infarction myocardial inflammation.
AuthorsNoureddine Loukili, Nathalie Rosenblatt-Velin, Jianhui Li, Stéphanie Clerc, Pal Pacher, François Feihl, Bernard Waeber, Lucas Liaudet
JournalCardiovascular research (Cardiovasc Res) Vol. 89 Issue 3 Pg. 586-94 (Feb 15 2011) ISSN: 1755-3245 [Electronic] England
PMID21113057 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Advanced Glycosylation End Product-Specific Receptor
  • HMGB1 Protein
  • Hbp1 protein, rat
  • Receptors, Immunologic
  • Tlr4 protein, mouse
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Peroxynitrous Acid
  • 3-nitrotyrosine
  • Tyrosine
  • Stk30 protein, mouse
  • Mitogen-Activated Protein Kinases
  • Advanced Glycosylation End Product-Specific Receptor
  • Animals
  • Apoptosis (drug effects, physiology)
  • Cells, Cultured
  • HMGB1 Protein (metabolism)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases (metabolism)
  • Myoblasts, Cardiac (drug effects, metabolism, pathology)
  • Myocardial Infarction (metabolism, pathology)
  • Necrosis
  • Peroxynitrous Acid (metabolism, pharmacology)
  • Rats
  • Rats, Wistar
  • Receptors, Immunologic (metabolism)
  • Toll-Like Receptor 4 (metabolism)
  • Tyrosine (analogs & derivatives, metabolism)
  • Up-Regulation (drug effects, physiology)

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