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The role of Akt and mitogen-activated protein kinase systems in the protective effect of poly(ADP-ribose) polymerase inhibition in Langendorff perfused and in isoproterenol-damaged rat hearts.

Abstract
Blocking poly(ADP-ribosyl)ation of nuclear proteins protects the heart from ischemia-reperfusion injury. In addition, activation of Akt and mitogen-activated protein kinase (MAPK) cascades also plays a pivotal role in the survival of cardiomyocytes during ischemia-reperfusion; however, the potential interplay between these pathways is yet to be elucidated. We therefore tested the hypothesis whether poly(ADP-ribose) polymerase (PARP) inhibition can modulate Akt and MAPK signaling of ischemic-reperfused rat hearts. A novel PARP inhibitor, L-2286 [2-[(2-piperidin-1-yletil)thio]quinazolin-4(3H)-one] was administered during ischemia-reperfusion in Langendorff perfused rat hearts and in isoproterenol-induced myocardial infarction. Thereafter, the cardiac energy metabolism, oxidative damage, and the phosphorylation state of Akt and MAPK cascades were monitored. L-2286 exerted significant protective effect against ischemia-reperfusion-induced myocardial injury in both experimental models. More importantly, L-2286 facilitated the ischemia-reperfusion-induced activation of Akt, extracellular signal-regulated kinase, and p38-MAPK in both isolated hearts and in vivo cardiac injury. By contrast, isoproterenol-induced rapid c-Jun N-termainal kinase activation was repressed by L-2286. Here, we provide evidence for the first time that PARP inhibition beneficially modulates the cardiac Akt and MAPK signaling in ex vivo and in vivo ischemia-reperfusion models. We therefore propose that this novel mechanism may contribute to the cardioprotective properties of PARP inhibitors.
AuthorsAnita Pálfi, Ambrus Tóth, Gyozo Kulcsár, Katalin Hantó, Péter Deres, Eva Bartha, Róbert Halmosi, Eszter Szabados, László Czopf, Tamás Kálai, Kálmán Hideg, Balázs Sümegi, Kálmán Tóth
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 315 Issue 1 Pg. 273-82 (Oct 2005) ISSN: 0022-3565 [Print] United States
PMID15951400 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one
  • Enzyme Inhibitors
  • Piperidines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protective Agents
  • Proteins
  • Quinazolines
  • Hydrogen Peroxide
  • Mitogen-Activated Protein Kinases
  • Isoproterenol
Topics
  • Animals
  • Energy Metabolism (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Heart (drug effects)
  • Hydrogen Peroxide (pharmacology)
  • Isoproterenol (toxicity)
  • Lipid Peroxidation (drug effects)
  • Male
  • Mitogen-Activated Protein Kinases (physiology)
  • Myocardium (metabolism)
  • Perfusion
  • Phosphorylation
  • Piperidines (pharmacology)
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protective Agents (pharmacology)
  • Proteins (metabolism)
  • Quinazolines (pharmacology)
  • Rats
  • Rats, Sprague-Dawley

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