title: 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.
authors.affiliation: First Department of Medicine, Division of Cardiology, University of Pécs, Pécs, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Pálfi
authors.forename: Ambrus
authors.initials: A
authors.lastname: Tóth
authors.forename: Gyozo
authors.initials: G
authors.lastname: Kulcsár
authors.forename: Katalin
authors.initials: K
authors.lastname: Hantó
authors.forename: Péter
authors.initials: P
authors.lastname: Deres
authors.forename: Eva
authors.initials: E
authors.lastname: Bartha
authors.forename: Róbert
authors.initials: R
authors.lastname: Halmosi
authors.forename: Eszter
authors.initials: E
authors.lastname: Szabados
authors.forename: László
authors.initials: L
authors.lastname: Czopf
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.forename: Balázs
authors.initials: B
authors.lastname: Sümegi
authors.forename: Kálmán
authors.initials: K
authors.lastname: Tóth
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007545:Isoproterenol / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D010477:Perfusion; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C505456:2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one; D004791:Enzyme Inhibitors; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents; D011506:Proteins; D011799:Quinazolines; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D007545:Isoproterenol