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

  • Authors:
    • Pál Pacher
    • Lucas Liaudet
    • Jon G. Mabley
    • Attila Cziráki
    • György Haskó
    • Csaba Szabó
  • View Affiliations

  • Published online on: February 1, 2006     https://doi.org/10.3892/ijmm.17.2.369
  • Pages: 369-375
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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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February 2006
Volume 17 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Pacher P, Liaudet L, Mabley JG, Cziráki A, Haskó G and Szabó C: Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure. Int J Mol Med 17: 369-375, 2006
APA
Pacher, P., Liaudet, L., Mabley, J.G., Cziráki, A., Haskó, G., & Szabó, C. (2006). Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure. International Journal of Molecular Medicine, 17, 369-375. https://doi.org/10.3892/ijmm.17.2.369
MLA
Pacher, P., Liaudet, L., Mabley, J. G., Cziráki, A., Haskó, G., Szabó, C."Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure". International Journal of Molecular Medicine 17.2 (2006): 369-375.
Chicago
Pacher, P., Liaudet, L., Mabley, J. G., Cziráki, A., Haskó, G., Szabó, C."Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure". International Journal of Molecular Medicine 17, no. 2 (2006): 369-375. https://doi.org/10.3892/ijmm.17.2.369