Document Detail

Peroxynitrite induces HMGB1 release by cardiac cells in vitro and HMGB1 upregulation in the infarcted myocardium in vivo.
MedLine Citation:
PMID:  21113057     Owner:  NLM     Status:  MEDLINE    
AIMS: 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.
METHODS AND RESULTS: 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.
CONCLUSION: 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.
Noureddine Loukili; Nathalie Rosenblatt-Velin; Jianhui Li; Stéphanie Clerc; Pal Pacher; François Feihl; Bernard Waeber; Lucas Liaudet
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2010-11-26
Journal Detail:
Title:  Cardiovascular research     Volume:  89     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-28     Completed Date:  2011-04-28     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  586-94     Citation Subset:  IM    
Department of Intensive Care Medicine, University Hospital Center and Faculty of Biology and Medicine, 1011 Lausanne, Switzerland.
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MeSH Terms
Apoptosis / drug effects,  physiology
Cells, Cultured
HMGB1 Protein / metabolism*
Mice, Inbred C57BL
Mitogen-Activated Protein Kinases / metabolism
Myoblasts, Cardiac / drug effects,  metabolism*,  pathology
Myocardial Infarction / metabolism*,  pathology
Peroxynitrous Acid / metabolism,  pharmacology*
Rats, Wistar
Receptors, Immunologic / metabolism
Toll-Like Receptor 4 / metabolism
Tyrosine / analogs & derivatives,  metabolism
Up-Regulation / drug effects,  physiology
Reg. No./Substance:
0/HMGB1 Protein; 0/Hbp1 protein, rat; 0/Receptors, Immunologic; 0/Tlr4 protein, mouse; 0/Tlr4 protein, rat; 0/Toll-Like Receptor 4; 0/advanced glycosylation end-product receptor; 14691-52-2/Peroxynitrous Acid; 3604-79-3/3-nitrotyrosine; 55520-40-6/Tyrosine; EC 2.7.1.-/Stk30 protein, mouse; EC Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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