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 Szabo, Márk Kollai, László Ligeti, Tamás Ivanics

Research output: Contribution to journalArticle

50 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 (US)
Pages (from-to)725-732
Number of pages8
JournalBiochemical Pharmacology
Volume69
Issue number5
DOIs
StatePublished - Mar 1 2005
Externally publishedYes

Fingerprint

Poly(ADP-ribose) Polymerases
Doxorubicin
Heart Failure
Calcium
Oxidative stress
Pharmacology
Hydrogen Peroxide
Oxidative Stress
Chemical activation
Reactive Nitrogen Species
Cardiovascular system
Enzyme Activation
Cardiovascular System
Oxidants
Rats
Reactive Oxygen Species
Myocardium
Wounds and Injuries
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Szenczi, O., Kemecsei, P., Holthuijsen, M. F. J., Van Riel, N. A. W., Van Der Vusse, G. J., Pacher, P., ... 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

Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure. / Szenczi, Orsolya; Kemecsei, Péter; Holthuijsen, Max F J; Van Riel, Natal A W; Van Der Vusse, Ger J.; Pacher, Pál; Szabo, Csaba; Kollai, Márk; Ligeti, László; Ivanics, Tamás.

In: Biochemical Pharmacology, Vol. 69, No. 5, 01.03.2005, p. 725-732.

Research output: Contribution to journalArticle

Szenczi, O, Kemecsei, P, Holthuijsen, MFJ, Van Riel, NAW, Van Der Vusse, GJ, Pacher, P, Szabo, C, Kollai, M, Ligeti, L & Ivanics, T 2005, 'Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure', Biochemical Pharmacology, vol. 69, no. 5, pp. 725-732. https://doi.org/10.1016/j.bcp.2004.11.023
Szenczi O, Kemecsei P, Holthuijsen MFJ, Van Riel NAW, Van Der Vusse GJ, Pacher P et al. Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure. Biochemical Pharmacology. 2005 Mar 1;69(5):725-732. https://doi.org/10.1016/j.bcp.2004.11.023
Szenczi, Orsolya ; Kemecsei, Péter ; Holthuijsen, Max F J ; Van Riel, Natal A W ; Van Der Vusse, Ger J. ; Pacher, Pál ; Szabo, Csaba ; Kollai, Márk ; Ligeti, László ; Ivanics, Tamás. / Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure. In: Biochemical Pharmacology. 2005 ; Vol. 69, No. 5. pp. 725-732.
@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 Szabo and M{\'a}rk Kollai and L{\'a}szl{\'o} Ligeti and Tam{\'a}s Ivanics",
year = "2005",
month = "3",
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",

}

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 - Szabo, Csaba

AU - Kollai, Márk

AU - Ligeti, László

AU - Ivanics, Tamás

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

UR - http://www.scopus.com/inward/record.url?scp=13844264114&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13844264114&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2004.11.023

DO - 10.1016/j.bcp.2004.11.023

M3 - Article

C2 - 15710350

AN - SCOPUS:13844264114

VL - 69

SP - 725

EP - 732

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 5

ER -