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CARDIOVASCULAR

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, Gyz Kulcsár, Katalin Hantó, Péter Deres, Éva Bartha, Róbert Halmosi, Eszter Szabados, László Czopf, Tamás Kálai, Kálmán Hideg, Balázs Sümegi, and Kálmán Tóth

First Department of Medicine, Division of Cardiology (A.P., K.H., P.D., E.B., R.H., E.S., L.C., K.T.), Department of Biochemistry and Medical Chemistry (A.P., A.T., K.H., P.D., B.S.), Department of Organic and Medicinal Chemistry (G.K., T.K., K.H.), Research Group for Mitochondrial Function and Mitochondrial Diseases, Hungarian Academy of Sciences (B.S.), School of Medicine, University of Pécs, Pécs, Hungary

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.

Address correspondence to: Dr. Kalman Toth, First Department of Medicine, Division of Cardiology, University of Pecs, 13 Ifjusag Str., H-7624 Pecs, Hungary. E-mail: kalman.toth{at}aok.pte.hu

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