Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents

Pál Pacher, Attila Cziráki, Jon G. Mabley, Lucas Liaudet, Lajos Papp, Csaba Szabó

    Research output: Contribution to journalArticle

    45 Scopus citations

    Abstract

    Reactive oxygen and nitrogen species are overproduced in the cardiovascular system during circulatory shock. Oxidant-induced cell injury involves the activation of poly(ADP-ribose) polymerase (PARP). Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the new potent phenanthridinone PARP inhibitor PJ34 [the hydrochloride salt of N-(oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide], we studied whether the impaired cardiac function in endotoxic shock is dependent upon the PARP pathway. Escherichia coli endotoxin (lipopolysaccharide, LPS) at 55mg/kg, i.p., induced a severe depression of the systolic and diastolic contractile function, tachycardia, and a reduction in mean arterial blood pressure in both rats and mice. Treatment with PJ34 significantly improved cardiac function and increased the survival of rodents. In addition, LPS-induced depression of left ventricular performance was significantly less pronounced in PARP-1 knockout mice (PARP-/-) as compared with their wild-type littermates (PARP+/+). Thus, PARP activation in the cardiovascular system is an important contributory factor to the cardiac collapse and death associated with endotoxin shock.

    Original languageEnglish (US)
    Pages (from-to)1785-1791
    Number of pages7
    JournalBiochemical Pharmacology
    Volume64
    Issue number12
    DOIs
    StatePublished - Dec 15 2002

    Keywords

    • Cardiac collapse
    • Cardiac function
    • Endotoxin
    • Poly(ADP-ribose) polymerase
    • Shock

    ASJC Scopus subject areas

    • Biochemistry
    • Pharmacology

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