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 Szabo, Christopher T. Salerno, Michael S. Mulligan

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)950-956
Number of pages7
JournalAnnals of Thoracic Surgery
Volume80
Issue number3
DOIs
StatePublished - Sep 2005
Externally publishedYes

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Poly(ADP-ribose) Polymerases
Allografts
Heart Transplantation
Heterotopic Transplantation
Staining and Labeling
Poly Adenosine Diphosphate Ribose
Norway
Intraperitoneal Injections
Immunosuppression
Cyclosporine
INO 1001
Rodentia
Heart Failure
Immunohistochemistry
Inflammation
Wounds and Injuries
Enzymes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Farivar, A. S., McCourtie, A. S., MacKinnon-Patterson, B. C., Woolley, S. M., Barnes, A. D., Chen, M., ... Mulligan, M. S. (2005). Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival. Annals of Thoracic Surgery, 80(3), 950-956. https://doi.org/10.1016/j.athoracsur.2005.02.035

Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival. / Farivar, Alexander S.; McCourtie, Anton S.; MacKinnon-Patterson, Brendan C.; Woolley, Steven M.; Barnes, Andrew D.; Chen, Min; Jagtap, Prakash; Szabo, Csaba; Salerno, Christopher T.; Mulligan, Michael S.

In: Annals of Thoracic Surgery, Vol. 80, No. 3, 09.2005, p. 950-956.

Research output: Contribution to journalArticle

Farivar, AS, McCourtie, AS, MacKinnon-Patterson, BC, Woolley, SM, Barnes, AD, Chen, M, Jagtap, P, Szabo, C, Salerno, CT & Mulligan, MS 2005, 'Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival', Annals of Thoracic Surgery, vol. 80, no. 3, pp. 950-956. https://doi.org/10.1016/j.athoracsur.2005.02.035
Farivar AS, McCourtie AS, MacKinnon-Patterson BC, Woolley SM, Barnes AD, Chen M et al. Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival. Annals of Thoracic Surgery. 2005 Sep;80(3):950-956. https://doi.org/10.1016/j.athoracsur.2005.02.035
Farivar, Alexander S. ; McCourtie, Anton S. ; MacKinnon-Patterson, Brendan C. ; Woolley, Steven M. ; Barnes, Andrew D. ; Chen, Min ; Jagtap, Prakash ; Szabo, Csaba ; Salerno, Christopher T. ; Mulligan, Michael S. / Poly (ADP) ribose polymerase inhibition improves rat cardiac allograft survival. In: Annals of Thoracic Surgery. 2005 ; Vol. 80, No. 3. pp. 950-956.
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abstract = "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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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 - Szabo, Csaba

AU - Salerno, Christopher T.

AU - Mulligan, Michael S.

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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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