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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 10, 2005; DOI: 10.1124/jpet.105.088336

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Received for publication April 22, 2005.
Revised June 8, 2005.
Accepted for publication June 8, 2005.

The role of Akt and MAP kinase systems in the protective effect of PARP inhibition in Langendorff perfused and in isoproterenol damaged rat hearts

Anita Palfi 1, Ambrus Toth 2, Gyozo Kulcsar 3, Katalin Hanto 4, Peter Deres 4, Eva Bartha 4, Robert Halmosi 4, Eszter Szabados 4, Laszlo Czopf 4, Tamas Kalai 3, Kalman Hideg 3, Balazs Sumegi 5, Kalman Toth 4*

1 School of Medicine, University of Pecs, First Department of Medicine 2 School of Medicine, University of Pecs, Department of Biochemistry and Medical Chemistry 3 University of Pecs, School of Medicine, Department of Organic and Medicinal Chemistry 4 University of Pecs, School of Medicine, First Department of Medicine 5 University of Pecs, School of Medicine, Department of Biochemistry and Medical Chemistry

* Address correspondence to: E-mail: kalman.toth{at}aok.pte.hu

Abstract

Objective: 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 PARP inhibition can modulate Akt and MAPK signaling of ischemic-reperfused rat hearts. Methods: A novel PARP inhibitor (L-2286) was administered during ischemia-reperfusion in Langendorff perfused rat hearts and in isoproterenol-induced myocardial infarction. Subsequently, the cardiac energy metabolism, oxidative damage and the phosphorylation state of Akt and MAPK cascades were monitored. Results: 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, ERK and p38-MAPK in both isolated hearts and in vivo cardiac injury. By contrast, isoproterenol-induced rapid JNK activation was repressed by L-2286. Conclusion: 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.


Key words: Akt, Ischemia-reperfusion, Mitogen activated protein kinases, Myocardium, Poly(ADP-ribose) polymerase inhibition, cardioprotection


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