Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure

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Serval ID
serval:BIB_7A9FDA4C3EDC
Type
Article: article from journal or magazin.
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Publications
Institution
Title
Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure
Journal
International Journal of Molecular Medicine
Author(s)
Pacher P., Liaudet L., Mabley J. G., Cziraki A., Hasko G., Szabo C.
ISSN
1107-3756 (Print)
Publication state
Published
Issued date
02/2006
Volume
17
Number
2
Pages
369-75
Language
english
Notes
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't --- Old month value: Feb
Abstract
Overactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) contributes to the development of cell dysfunction and tissue injury in various pathophysiological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury, heart transplantation, diabetic cardiomyopathy and chronic heart failure. In recent studies, we have demonstrated the beneficial effects of a novel ultrapotent PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction and remodeling in rat model of advanced aging-associated chronic heart failure and in a mouse model of heart failure induced by aortic banding. In the current study, we have investigated the effect of INO-1001 on the development of heart failure induced by permanent ligation of the left anterior descending coronary artery, heart failure induced by doxorubicin and acute myocardial dysfunction induced by bacterial endotoxin. In the coronary ligation model, a significantly depressed left ventricular performance and impaired vascular relaxation of aortic rings were found, and PARP inhibition significantly improved both cardiac function and vascular relaxation. In the doxorubicin model, a single injection of doxorubicin induced high mortality and a significant decrease in left ventricular systolic pressure, +dP/dt, -dP/dt, stroke volume, stroke work, ejection fraction and cardiac output. Treatment with the PARP inhibitor reduced doxorubicin-induced mortality and markedly improved cardiac function. PARP inhibition did not interfere with doxorubicin's antitumor effect. In the endotoxin model of cardiac dysfunction, PARP inhibition attenuated the suppression of myocardial contractility elicited by endotoxin. The current data strengthen the view that PARP inhibition may represent an effective approach for the experimental therapy of various forms of acute and chronic heart failure.
Keywords
Animals Coronary Vessels/drug effects/metabolism *Disease Models, Animal Doxorubicin/pharmacology Enzyme Inhibitors/*pharmacology/*therapeutic use Heart Diseases/chemically induced/*drug therapy/*enzymology Indoles/*pharmacology Male Mice Mice, Inbred BALB C Poly(ADP-ribose) Polymerases/*antagonists & inhibitors/metabolism Survival Rate
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Web of science
Create date
24/01/2008 17:01
Last modification date
20/08/2019 14:36
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