Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure.
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.
Szenczi
Orsolya
O
Department of Human Physiology and Clinical Experimental Research, Semmelweis University Medical School, Ulloi ut 78/a, Budapest 1082, Hungary.
Kemecsei
Péter
P
Holthuijsen
Max F J
MF
van Riel
Natal A W
NA
van der Vusse
Ger J
GJ
Pacher
Pál
P
Szabó
Csaba
C
Kollai
Márk
M
Ligeti
László
L
Ivanics
Tamás
T
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity*; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D002118:Calcium