Abstract | 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:
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Authors | Noureddine Loukili, Nathalie Rosenblatt-Velin, Jianhui Li, Stéphanie Clerc, Pal Pacher, François Feihl, Bernard Waeber, Lucas Liaudet |
Journal | Cardiovascular research
(Cardiovasc Res)
Vol. 89
Issue 3
Pg. 586-94
(Feb 15 2011)
ISSN: 1755-3245 [Electronic] England |
PMID | 21113057
(Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- HMGB1 Protein
- Hbp1 protein, rat
- Receptor for Advanced Glycation End Products
- Receptors, Immunologic
- Tlr4 protein, mouse
- Tlr4 protein, rat
- Toll-Like Receptor 4
- Peroxynitrous Acid
- 3-nitrotyrosine
- Tyrosine
- Mok protein, mouse
- Mitogen-Activated Protein Kinases
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Topics |
- 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
- Receptor for Advanced Glycation End Products
- Receptors, Immunologic
(metabolism)
- Toll-Like Receptor 4
(metabolism)
- Tyrosine
(analogs & derivatives, metabolism)
- Up-Regulation
(drug effects, physiology)
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