Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival

Alexander S. Farivar, Anton S. McCourtie, Brendan C. MacKinnon-Patterson, Steven M. Woolley, Andrew D. Barnes, Min Chen, Prakash Jagtap, Csaba Szabó, Christopher T. Salerno, Michael S. Mulligan

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    17 Scopus citations

    Abstract

    Background. Heart transplantation is an accepted treatment modality for end-stage heart failure. However, acute cellular rejection (ACR) continues to be a morbid complication. Recently a novel mechanism of inflammatory allograft injury has been characterized which involves overactivation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP). In the present studies, we compared the efficacy of INO-1001, a novel, potent PARP inhibitor, in limiting ACR with and without adjuvant low-dose cyclosporine (CSA). Methods. Heterotopic heart transplantation was performed utilizing Brown-Norway strains as donors and Lewis rats as recipients. Groups received daily intraperitoneal injections of: vehicle, low-dose CSA, low-dose INO-1001, high-dose INO-1001, and low-dose CSA combined with high-dose INO-1001. Additional animals were sacrificed on postoperative Day 5 for histologic assessments of allograft inflammation, including immunohistochemistry for nitrotyrosine and poly (ADP-ribose) (the product of PARP) staining. Results. PARP inhibition significantly prolonged allograft survival relative to vehicle controls. The combination of low-dose CSA and INO-1001 resulted in a marked increase in allograft survival and significant reductions in allograft rejection scores. This was associated with decreased nitrotyrosine and PAR staining in transplanted cardiac allografts. Conclusions. Pharmacologic inhibition of INO-1001 prolongs allograft survival in a dose-dependent fashion in a rodent model of heart transplantation. PARP inhibitors may permit reductions in the dose of CSA needed for adequate immunosuppression after heart transplantation.

    Original languageEnglish (US)
    Pages (from-to)950-956
    Number of pages7
    JournalAnnals of Thoracic Surgery
    Volume80
    Issue number3
    DOIs
    StatePublished - Sep 1 2005

    ASJC Scopus subject areas

    • Surgery
    • Pulmonary and Respiratory Medicine
    • Cardiology and Cardiovascular Medicine

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  • Cite this

    Farivar, A. S., McCourtie, A. S., MacKinnon-Patterson, B. C., Woolley, S. M., Barnes, A. D., Chen, M., Jagtap, P., Szabó, C., Salerno, C. T., & Mulligan, M. S. (2005). Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival. Annals of Thoracic Surgery, 80(3), 950-956. https://doi.org/10.1016/j.athoracsur.2005.02.035