TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 273 LP - 282 DO - 10.1124/jpet.105.088336 VL - 315 IS - 1 AU - Anita Pálfi AU - Ambrus Tóth AU - Győző Kulcsár AU - Katalin Hantó AU - Péter Deres AU - Éva Bartha AU - Róbert Halmosi AU - Eszter Szabados AU - László Czopf AU - Tamás Kálai AU - Kálmán Hideg AU - Balázs Sümegi AU - Kálmán Tóth Y1 - 2005/10/01 UR - http://jpet.aspetjournals.org/content/315/1/273.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -