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Ann Thorac Surg 2005;80:950-956
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Poly (ADP) Ribose Polymerase Inhibition Improves Rat Cardiac Allograft Survival

^a University of Washington Medical Center, Department of Surgery, Division of Cardiothoracic Surgery, Seattle, Washington
^b Inotek Pharmaceuticals Corp, Beverly, Massachusetts

Accepted for publication February 7, 2005.

^_* Address reprint requests to Dr Mulligan, Department of Cardiothoracic Surgery, Box 356310, University of Washington Medical Center, 1959 NE Pacific St, Seattle, WA 98195 (Email: msmmd{at}u.washington.edu).

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.

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