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Tetramethylphenylenediamine protects the isolated heart against ischaemia‐induced apoptosis and reperfusion‐induced necrosis
Author(s) -
Barauskaite Jurgita,
Grybauskiene Regina,
Morkuniene Ramune,
Borutaite Vilmante,
Brown Guy C
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01110.x
Subject(s) - necrosis , apoptosis , ischemia , medicine , cardiology , myocardial reperfusion injury , pharmacology , reperfusion injury , chemistry , biochemistry
BACKGROUND AND PURPOSE Cytochrome c when released from mitochondria into cytosol triggers assembly of the apoptosome resulting in caspase activation. Recent evidence suggests that reduced cytochrome c is unable to activate the caspase cascade. In this study, we investigated whether a chemical reductant of cytochrome c , N,N,N′,N′‐tetramethylphenylene‐1,4‐diamine (TMPD), which we have previously shown to block cytochrome c ‐induced caspase activation, could prevent ischaemia‐induced apoptosis in the rat perfused heart. EXPERIMENTAL APPROACH The Langendorff‐perfused rat hearts were pretreated with TMPD and subjected to stop‐flow ischaemia or ischaemia/reperfusion. The activation of caspases (measured as DEVD‐p‐nitroanilide‐cleaving activity), nuclear apoptosis of cardiomyocytes (measured by dUTP nick end labelling assay), mitochondrial and cytosolic levels of cytochrome c (measured spectrophotometrically and by elisa ), and reperfusion‐induced necrosis (measured as the activity of creatine kinase released into perfusate) were assessed. KEY RESULTS We found that perfusion of the hearts with TMPD strongly inhibited ischaemia‐ or ischaemia/reperfusion‐induced activation of caspases and partially prevented nuclear apoptosis in cardiomyocytes. TMPD did not prevent ischaemia‐ or ischaemia/reperfusion‐induced release of cytochrome c from mitochondria into cytosol. TMPD also inhibited ischaemia/reperfusion‐induced necrosis. CONCLUSIONS AND IMPLICATIONS These results suggest that TMPD or related molecules might be used to protect the heart against damage induced by ischaemia/reperfusion. The mechanism of this protective effect of TMPD probably involves electron reduction of cytochrome c (without decreasing its release) which then inhibits the activation of caspases.