Regulation of kinase cascade activation and heat shock protein expression by poly(ADP-ribose) polymerase inhibition in doxorubicin-induced heart failure

Eva Bartha, Izabella Solti, Aliz Szabo, Gabor Olah, Klara Magyar, Eszter Szabados, Tamas Kalai, Kalman Hideg, Kalman Toth, Domokos Gero, Csaba Szabo, Balazs Sumegi, Robert Halmosi

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19 Scopus citations

Abstract

Cardiomyopathy is one of the most severe side effects of the chemotherapeutic agent doxorubicin (DOX). The formation of reactive oxygen species plays a critical role in the development of cardiomyopathies, and the pathophysiological cascade activates nuclear enzyme poly(ADP-ribose) polymerase (PARP), and kinase pathways. We characterized the effects of the PARP-inhibitor and kinase-modulator compound L-2286 in DOX-induced cardiac injury models. We studied the effect of the established superoxide dismutase-mimic Tempol and compared the effects of this agent with those of the PARP inhibitor. In the rat H9C2 cardiomyocytes, in which DOX-induced poly(ADP-ribosyl)ation, L-2286 protected them from the DOX-induced injury in a concentration-dependent manner. In the in vivo studies, mice were pretreated (for 1 week) with L-2286 or Tempol before the DOX treatment. Both the agents improved the activation of cytoprotective kinases, Akt, phospho-specific protein kinase C ε, ζ/λ and suppressed the activity of cell death promoting kinases glycogen synthase kinase-3β, JNK, and p38 mitogen-activated protein kinase, but the effect of PARP inhibitor was more pronounced and improved the survival as well. L-2286 activated the phosphorylation of proapoptotic transcription factor FKHR1 and promoted the expression of Hsp72 and Hsp90. These data suggest that the mode of the cytoprotective action of the PARP inhibitor may include the modulation of kinase pathways and heat shock protein expression.

Original languageEnglish (US)
Pages (from-to)380-391
Number of pages12
JournalJournal of cardiovascular pharmacology
Volume58
Issue number4
DOIs
StatePublished - Oct 1 2011

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Keywords

  • cardiomyopathy
  • doxorubicin
  • echocardiography
  • intracellular signaling

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Bartha, E., Solti, I., Szabo, A., Olah, G., Magyar, K., Szabados, E., Kalai, T., Hideg, K., Toth, K., Gero, D., Szabo, C., Sumegi, B., & Halmosi, R. (2011). Regulation of kinase cascade activation and heat shock protein expression by poly(ADP-ribose) polymerase inhibition in doxorubicin-induced heart failure. Journal of cardiovascular pharmacology, 58(4), 380-391. https://doi.org/10.1097/FJC.0b013e318225c21e