Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation

Gábor Szabó, Susanne Bährle, Nicole Stumpf, Karin Sonnenberg, Éva Szabó, Pál Pacher, Tamás Csont, Richard Schulz, Thomas J. Dengler, Lucas Liaudet, Prakash G. Jagtap, Garry J. Southan, Christian F. Vahl, Siegfried Hagl, Csaba Szabó

    Research output: Contribution to journalArticle

    146 Scopus citations

    Abstract

    The aim of the present study was to investigate the effects of the novel poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide) on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After a 1-hour ischemic preservation, reperfusion was started either after application of placebo or PJ34 (3 mg/kg). The assessment of left ventricular pressure-volume relations, total coronary blood flow, endothelial function, myocardial high energy phosphates, and histological analysis were performed at 1 and 24 hours of reperfusion. After 1 hour, myocardial contractility and relaxation, coronary blood flow, and endothelial function were significantly improved and myocardial high energy phosphate content was preserved in the PJ34-treated animals. Improved transplant function was also seen with treatment with another, structurally different PARP inhibitor, 5-aminoisoquinoline. The PARP inhibitors did not affect baseline cardiac function. Immunohistological staining confirmed that PJ34 prevented the activation of PARP in the transplanted hearts. The activation of P-selectin and ICAM-1 was significantly elevated in the vehicle-treated heart transplantation group. Thus, pharmacological PARP inhibition reduces reperfusion injury after heart transplantation due to prevention of energy depletion and downregulation of adhesion molecules and exerts a beneficial effect against reperfusion-induced graft coronary endothelial dysfunction.

    Original languageEnglish (US)
    Pages (from-to)100-106
    Number of pages7
    JournalCirculation Research
    Volume90
    Issue number1
    DOIs
    StatePublished - Jan 11 2002

    Keywords

    • Endothelial function
    • PARP inhibition
    • Rat
    • Reperfusion injury
    • Transplantation

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine

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  • Cite this

    Szabó, G., Bährle, S., Stumpf, N., Sonnenberg, K., Szabó, É., Pacher, P., Csont, T., Schulz, R., Dengler, T. J., Liaudet, L., Jagtap, P. G., Southan, G. J., Vahl, C. F., Hagl, S., & Szabó, C. (2002). Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation. Circulation Research, 90(1), 100-106. https://doi.org/10.1161/hh0102.102657