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Tetramethylphenylenediamine protects the isolated heart against ischaemia-induced apoptosis and reperfusion-induced necrosis.

AbstractBACKGROUND 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.
AuthorsJurgita Barauskaite, Regina Grybauskiene, Ramune Morkuniene, Vilmante Borutaite, Guy C Brown
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 162 Issue 5 Pg. 1136-42 (Mar 2011) ISSN: 1476-5381 [Electronic] England
PMID21077848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Chemical References
  • Cardiotonic Agents
  • Cytochromes c
  • Caspases
  • Tetramethylphenylenediamine
Topics
  • Animals
  • Apoptosis (drug effects)
  • Cardiotonic Agents (pharmacology)
  • Caspases (metabolism)
  • Cytochromes c (metabolism)
  • Cytosol (metabolism)
  • Enzyme Activation (drug effects)
  • In Vitro Techniques
  • Male
  • Mitochondria, Heart (drug effects, metabolism)
  • Myocardial Reperfusion Injury (metabolism, pathology, prevention & control)
  • Necrosis (prevention & control)
  • Rats
  • Rats, Wistar
  • Tetramethylphenylenediamine (pharmacology)

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