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

P. Pacher, L. Liaudet, Jon Mabley, A. Cziraki, G. Hasko, C. Szabo

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)369-375
Number of pages7
JournalInternational Journal of Molecular Medicine
Volume17
Issue number2
Publication statusPublished - 28 Feb 2006

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Poly(ADP-ribose) Polymerases
Doxorubicin
Heart Failure
Endotoxins
Ligation
Blood Vessels
Diabetic Cardiomyopathies
Myocardial Reperfusion Injury
Investigational Therapies
Mortality
Ventricular Pressure
Heart Transplantation
Cardiac Output
Stroke Volume
Poly(ADP-ribose) Polymerase Inhibitors
Coronary Vessels
Oxidative Stress
Stroke
Blood Pressure
Injections

Cite this

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title = "Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure",
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.",
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Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure. / Pacher, P.; Liaudet, L.; Mabley, Jon; Cziraki, A.; Hasko, G.; Szabo, C.

In: International Journal of Molecular Medicine, Vol. 17, No. 2, 28.02.2006, p. 369-375.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Pacher, P.

AU - Liaudet, L.

AU - Mabley, Jon

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AU - Hasko, G.

AU - Szabo, C.

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