Poly (ADP) Ribose Polymerase Inhibition Improves Rat Cardiac Allograft Survival
| Autor: | Alexander S. Farivar, Michael S. Mulligan, Christopher T. Salerno, Prakash Jagtap, Brendan C. Mackinnon-Patterson, Steven M Woolley, Andrew D. Barnes, Min Chen, Anton S. McCourtie, Csaba Szabó |
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| Rok vydání: | 2005 |
| Předmět: |
Pulmonary and Respiratory Medicine
Pathology medicine.medical_specialty Indoles medicine.medical_treatment Poly ADP ribose polymerase Poly(ADP-ribose) Polymerase Inhibitors Pharmacology Inferior vena cava chemistry.chemical_compound medicine Animals Enzyme Inhibitors Heart transplantation Dose-Response Relationship Drug business.industry Nitrotyrosine Graft Survival Immunosuppression medicine.disease Rats Transplantation Disease Models Animal surgical procedures operative chemistry medicine.vein Rats Inbred Lew Heart failure PARP inhibitor Cyclosporine Heart Transplantation Tyrosine Drug Therapy Combination Surgery Poly(ADP-ribose) Polymerases Cardiology and Cardiovascular Medicine business |
| Zdroj: | The Annals of Thoracic Surgery. 80:950-956 |
| ISSN: | 0003-4975 |
| DOI: | 10.1016/j.athoracsur.2005.02.035 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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