Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury

Basilia Zingarelli, Andrew L. Salzman, Csaba Szabó

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    301 Scopus citations

    Abstract

    The nuclear enzyme poly (ADP-ribose) synthetase (PARS) has been shown to play an important role in the pathogenesis of ischemia/reperfusion injury and circulatory shock. The aim of this study was to investigate whether PARS activity may modulate endothelial-neutrophil interaction. We present evidence that genetic disruption of PARS provides protection against myocardial ischemia and reperfusion injury by inhibiting the expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) and, consequently, by inhibiting the recruitment of neutrophils into the jeopardized tissue. Furthermore, using in vitro studies, we demonstrate that in fibroblasts lacking a functional gene for PARS, cytokine-stimulated expression of ICAM-1 is significantly reduced compared with fibroblasts from animals with a normal genotype. Similarly, in cultured human endothelial cells, oxidative- or cytokine-dependent expression of P-selectin and ICAM-1 is reduced by pharmacological inhibition of PARS by 3-aminobenzamide. These findings provide the first direct evidence that PARS activation participates in neutrophil-mediated myocardial damage by regulating the expression of P- selectin and ICAM-1 in ischemic and reperfused myocardium, and they also provide the basis for a novel therapeutic approach for the treatment of reperfusion injury.

    Original languageEnglish (US)
    Pages (from-to)85-94
    Number of pages10
    JournalCirculation Research
    Volume83
    Issue number1
    DOIs
    StatePublished - Jul 13 1998

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    Keywords

    • 3- aminobenzamide
    • Cell adhesion molecule
    • Neutrophil
    • Nitric oxide
    • Peroxynitrite

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine

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