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

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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.

Original languageEnglish
Pages (from-to)273-282
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume315
Issue number1
DOIs
Publication statusPublished - Oct 1 2005

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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