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

O. Szenczi, P. Kemecsei, M.F.J. Holthuijsen, N.A.W. Riel, van, G.J. Vusse, van der, P. Pacher, C. Szabo, M. Kollai, L. Ligeti, T. Ivanics

Research output: Contribution to journalArticleAcademicpeer-review

52 Citations (Scopus)

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
Pages (from-to)725-732
Number of pages8
JournalBiochemical Pharmacology
Volume69
Issue number5
DOIs
Publication statusPublished - 2005

Fingerprint

Dive into the research topics of 'Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure'. Together they form a unique fingerprint.

Cite this