Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 41, Issue 6, Pages 886-895Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2006.04.034
Keywords
peroxynitrite; apoptosis; necrosis; poly(ADP-ribose) polymerase; caspase; myocardium; cardiomyocyte
Funding
- Intramural NIH HHS [Z01 AA000375-02] Funding Source: Medline
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Recent evidence indicates that peroxynitrite represents a major cytotoxic effector in heart diseases, but its mechanisms of action are still not known exactly. Notably, the ability of peroxynitrite to trigger cardiomyocyte apoptosis, a crucial mode of cell death in many cardiac conditions, remains poorly defined. We evaluated apoptotic and necrotic cell death in cultured H9C2 cardiomyocytes, following a brief (20 min) exposure to peroxynitrite (50-500 mu M). Peroxynitrite-dependent myocardial toxicity was then investigated in a rat model of myocardial ischemia-reperfusion (MIR), where the effects of peroxynitrite were blocked by the superoxide dismutase mimetics and peroxynitrite scavenger Mn(III)-tetrakis(4-benzoic acid) porphyrin (MnTBAP). In vitro, peroxynitrite killed cardiomyocytes mostly through apoptosis (DNA fragmentation, apoptotic nuclear alterations, caspase-3 activation, and PARP cleavage), but not necrosis (propidium iodide staining and LDH release). In vivo, MIR triggered myocardial oxidative stress (malondialdehyde generation), nitrotyrosine formation, neutrophil accumulation, and the cleavage of caspase-3 and PARP, indicating ongoing myocardial apoptosis. MnTBAP suppressed these alterations, allowing a considerable reduction of myocardial injury. Thus, peroxynitrite triggers apoptosis in cardiomyocytes in vitro and in the myocardium in vivo, through a pathway involving caspase-3 activation and the cleavage of PARR These results provide important novel information on the mechanisms of myocardial toxicity of peroxynitrite. (c) 2006 Published by Elsevier Inc.
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