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

Anita Pálfi, Ambrus Tóth, Gyozo Kulcsár, Katalin Hantó, Péter Deres, Éva Bartha, Róbert Halmosi, Eszter Szabados, László Czopf, Tamás Kálai, Kálmán Hideg, Balázs Sümegi, Kálmán Tóth

Research output: Contribution to journalArticle

41 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)273-282
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
Publication statusPublished - Oct 1 2005


ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this