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

doi:10.1016/j.bcp.2004.11.023

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 journal › Article › peer-review

63 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 language	English (US)
Pages (from-to)	725-732
Number of pages	8
Journal	Biochemical Pharmacology
Volume	69
Issue number	5
DOIs	https://doi.org/10.1016/j.bcp.2004.11.023
State	Published - Mar 1 2005
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Biochemistry
Pharmacology

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10.1016/j.bcp.2004.11.023

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@article{2eafc368d1314f889e0de82799f5ec30,

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

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.",

keywords = "Adriamycin, Calcium, Heart failure, Peroxynitrite, Poly(ADP-ribose) polymerase (PARP), Superoxide",

author = "Orsolya Szenczi and P{\'e}ter Kemecsei and Holthuijsen, {Max F.J.} and {Van Riel}, {Natal A.W.} and {Van Der Vusse}, {Ger J.} and P{\'a}l Pacher and Csaba Szab{\'o} and M{\'a}rk Kollai and L{\'a}szl{\'o} Ligeti and Tam{\'a}s Ivanics",

note = "Funding Information: This work was supported by grants from OTKA (Hungarian Research Fund, T038121, T047095 and T042969) and the National Institutes of Health (R01 HL 59266) and by the Socrates program of the European Community and the Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.",

year = "2005",

month = mar,

day = "1",

doi = "10.1016/j.bcp.2004.11.023",

language = "English (US)",

volume = "69",

pages = "725--732",

journal = "Biochemical Pharmacology",

issn = "0006-2952",

publisher = "Elsevier Inc.",

number = "5",

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TY - JOUR

T1 - Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure

AU - Szenczi, Orsolya

AU - Kemecsei, Péter

AU - Holthuijsen, Max F.J.

AU - Van Riel, Natal A.W.

AU - Van Der Vusse, Ger J.

AU - Pacher, Pál

AU - Szabó, Csaba

AU - Kollai, Márk

AU - Ligeti, László

AU - Ivanics, Tamás

N1 - Funding Information: This work was supported by grants from OTKA (Hungarian Research Fund, T038121, T047095 and T042969) and the National Institutes of Health (R01 HL 59266) and by the Socrates program of the European Community and the Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.

PY - 2005/3/1

Y1 - 2005/3/1

N2 - 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.

AB - 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.

KW - Adriamycin

KW - Calcium

KW - Heart failure

KW - Peroxynitrite

KW - Poly(ADP-ribose) polymerase (PARP)

KW - Superoxide

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DO - 10.1016/j.bcp.2004.11.023

M3 - Article

C2 - 15710350

AN - SCOPUS:13844264114

SN - 0006-2952

VL - 69

SP - 725

EP - 732

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

IS - 5

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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