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 journalArticle

    51 Scopus citations

    Abstract

    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
    Volume69
    Issue number5
    DOIs
    StatePublished - Mar 1 2005

    Keywords

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

    ASJC Scopus subject areas

    • Biochemistry
    • Pharmacology

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  • Cite this

    Szenczi, O., Kemecsei, P., Holthuijsen, M. F. J., Van Riel, N. A. W., Van Der Vusse, G. J., Pacher, P., Szabó, C., Kollai, M., Ligeti, L., & Ivanics, T. (2005). Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure. Biochemical Pharmacology, 69(5), 725-732. https://doi.org/10.1016/j.bcp.2004.11.023