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

doi:10.1016/j.athoracsur.2005.02.035

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

Journal article

Peer reviewed

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 and Michael S Mulligan

The Annals of thoracic surgery, Vol.80(3), pp.950-956

09/2005

DOI: 10.1016/j.athoracsur.2005.02.035

PMID: 16122462

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Abstract

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). 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. 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. 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.

Rats, Inbred Lew

Rats

Graft Survival

Heart Transplantation

Enzyme Inhibitors - therapeutic use

Poly(ADP-ribose) Polymerase Inhibitors

Tyrosine - analogs & derivatives

Dose-Response Relationship, Drug

Cyclosporine - therapeutic use

Poly(ADP-ribose) Polymerases - metabolism

Tyrosine - metabolism

Animals

Indoles - therapeutic use

Drug Therapy, Combination

Disease Models, Animal

Details

Title: Subtitle: Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival
Creators: Alexander S Farivar - Division of Cardiothoracic Surgery, Department of Surgery, University of Washington Medical Center, Seattle, Washington 98195, USA
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
Resource Type: Journal article
Publication Details: The Annals of thoracic surgery, Vol.80(3), pp.950-956
DOI: 10.1016/j.athoracsur.2005.02.035
PMID: 16122462
NLM abbreviation: Ann Thorac Surg
ISSN: 0003-4975
eISSN: 1552-6259
Publisher: Netherlands
Grant note: R43 HL69419 / NHLBI NIH HHS
Language: English
Date published: 09/2005
Academic Unit: Orthopedics and Rehabilitation
Record Identifier: 9984040599402771

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