Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure

Orsolya Szenczi, Péter Kemecsei, Max F.J. Holthuijsen, Natal A.W. Van Riel, Ger J. Van Der Vusse, Pál Pacher, Csaba Szabó, Márk Kollai, László Ligeti, Tamás Ivanics

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


Reactive oxygen and nitrogen species are overproduced in the cardiovascular system in response to the exposure to doxorubicin, a cardiotoxic anticancer compound. Oxidant-induced cell injury involves the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and pharmacological inhibition of PARP has recently been shown to improve myocardial contractility in doxorubicin-induced heart failure models. The current investigation, by utilizing an isolated perfused heart system capable of beat-to-beat intracellular calcium recording, addressed the following questions: (1) is intracellular calcium handling altered in hearts of rats after 6-week doxorubicin treatment, under baseline conditions, and in response to oxidative stress induced by hydrogen peroxide exposure in vitro; and (2) does pharmacological inhibition of PARP with the phenanthridinone-based PARP inhibitor PJ34 affect the changes in myocardial mechanical performance and calcium handling in doxorubicin-treated hearts under normal conditions and in response to oxidative stress. The results showed a marked elevation in intracellular calcium in the doxorubicin-treated hearts which was normalized by pharmacological inhibition of PARP. PARP inhibition also prevented the myocardial contractile disturbances and calcium overload that developed in response to hydrogen peroxide in the doxorubicin-treated hearts. We conclude that PARP activation contributes to the development of the disturbances in cellular calcium handling that develop in the myocardium in response to prolonged doxorubicin exposure.

Original languageEnglish (US)
Pages (from-to)725-732
Number of pages8
JournalBiochemical Pharmacology
Issue number5
StatePublished - Mar 1 2005
Externally publishedYes


  • Adriamycin
  • Calcium
  • Heart failure
  • Peroxynitrite
  • Poly(ADP-ribose) polymerase (PARP)
  • Superoxide

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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