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, Katalin Komjáti, Csaba Szabó

    Research output: Contribution to journalArticlepeer-review

    100 Scopus citations

    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 (US)
    Pages (from-to)1006-1016
    Number of pages11
    JournalJournal of the American College of Cardiology
    Volume40
    Issue number5
    DOIs
    StatePublished - Sep 4 2002

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

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