TY - JOUR
T1 - Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival
AU - Farivar, Alexander S.
AU - McCourtie, Anton S.
AU - MacKinnon-Patterson, Brendan C.
AU - Woolley, Steven M.
AU - Barnes, Andrew D.
AU - Chen, Min
AU - Jagtap, Prakash
AU - Szabó, Csaba
AU - Salerno, Christopher T.
AU - Mulligan, Michael S.
N1 - Funding Information:
This work was funded by a grant from the National Institutes of Health (R43 HL69419) to Dr Jagtap.
PY - 2005/9
Y1 - 2005/9
N2 - 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.
AB - 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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U2 - 10.1016/j.athoracsur.2005.02.035
DO - 10.1016/j.athoracsur.2005.02.035
M3 - Article
C2 - 16122462
AN - SCOPUS:23944526864
SN - 0003-4975
VL - 80
SP - 950
EP - 956
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
IS - 3
ER -