Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure

Pál Pacher, Lucas Liaudet, Jon G. Mabley, K. Komjáti, Csaba Szabó

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Abstract

OBJECTIVES. We investigated the effects of a novel ultrapotent poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, PJ34, on cardiac and endothelial dysfunction in a rat model of chronic heart failure (CHF). BACKGROUND. Overactivation of the nuclear enzyme PARP importantly contributes to the development of cell dysfunction and tissue injury in various pathophysiologic conditions associated with oxidative stress, including myocardial reperfusion injury, heart transplantation, stroke, shock, and diabetes. METHODS. Chronic heart failure was induced in Wistar rats by chronic ligation of the left anterior descending coronary artery. Left ventricular (LV) function and ex vivo vascular contractility and relaxation were measured 10 weeks after the surgery. Nitrotyrosine (NT) formation and PARP activation were detected by immunohistochemistry. RESULTS. Chronic heart failure induced increased NT formation and PARP activation in the myocardium and intramural vasculature, depressed LV performance, and impaired vascular relaxation of aortic rings. PJ34 significantly decreased myocardial PARP activation but not NT formation, and improved both cardiac dysfunction and vascular relaxation. CONCLUSIONS. Poly(ADP-ribose) polymerase inhibition represents a novel approach for the experimental treatment of CHF.

Original languageEnglish
Pages (from-to)1006-1016
Number of pages11
JournalJournal of the American College of Cardiology
Volume40
Issue number5
DOIs
Publication statusPublished - Sep 4 2002

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Adenosine Diphosphate Ribose
Poly Adenosine Diphosphate Ribose
Heart Failure
Blood Vessels
Myocardial Reperfusion Injury
Poly(ADP-ribose) Polymerases
Heart Transplantation
Therapeutics
Left Ventricular Function
Ligation
Wistar Rats
Shock
Coronary Vessels
Myocardium
Oxidative Stress
Immunohistochemistry
Stroke
Wounds and Injuries
Enzymes
3-nitrotyrosine

ASJC Scopus subject areas

  • Nursing(all)

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Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure. / Pacher, Pál; Liaudet, Lucas; Mabley, Jon G.; Komjáti, K.; Szabó, Csaba.

In: Journal of the American College of Cardiology, Vol. 40, No. 5, 04.09.2002, p. 1006-1016.

Research output: Contribution to journalArticle

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