Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival.
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.
Farivar
Alexander S
AS
Division of Cardiothoracic Surgery, Department of Surgery, University of Washington Medical Center, Seattle, Washington 98195, USA.
McCourtie
Anton S
AS
MacKinnon-Patterson
Brendan C
BC
Woolley
Steven M
SM
Barnes
Andrew D
AD
Chen
Min
M
Jagtap
Prakash
P
Szabó
Csaba
C
Salerno
Christopher T
CT
Mulligan
Michael S
MS
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006085:Graft Survival; D016027:Heart Transplantation; D007211:Indoles / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D004791:Enzyme Inhibitors; C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C002744:3-nitrotyrosine; D014443:Tyrosine; D016572:Cyclosporine; D011065:Poly(ADP-ribose) Polymerases