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

Ann Thorac Surg. 2005 Sep;80(3):950-6. doi: 10.1016/j.athoracsur.2005.02.035.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cyclosporine / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Enzyme Inhibitors / therapeutic use
  • Graft Survival*
  • Heart Transplantation*
  • Indoles / therapeutic use
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Rats
  • Rats, Inbred Lew
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism


  • Enzyme Inhibitors
  • INO 1001
  • Indoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • 3-nitrotyrosine
  • Tyrosine
  • Cyclosporine
  • Poly(ADP-ribose) Polymerases