Immunomodulatory Effects of Poly(ADP-ribose) Polymerase Inhibition Contribute to Improved Cardiac Function and Survival During Acute Cardiac Rejection

Gábor Szabó, Susanne Bährle, Vijayshankar Sivanandam, Nicole Stumpf, Domokos Gerö, Irina Berger, Carsten Beller, Siegfried Hagl, Csaba Szabo, Thomas J. Dengler

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Recent studies have suggested that the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway is activated during acute allograft rejection. Therefore, we investigated whether PARP inhibition improves transplant outcome and the extent to which immunologic factors contribute to the effects of PARP inhibition. Methods: Isogeneic Lewis-to-Lewis and allogeneic Dark Agouti (DA)-to-Lewis rat cardiac transplants were studied under treatment with placebo, the PARP inhibitor INO-1001 (1 mg/kg/day), cyclosporine (2.5 or 5 mg/kg/day) or the combination of INO-1001 and low-dose cyclosporine. Functional, biochemical and histologic analyses were performed 3 and 5 days after transplantation in control and INO-1001-treated animals. In addition, stimulated T cells and endothelial cells were treated with INO-1001 to evaluate the potential immunosuppressive effects of PARP inhibition. Results: PARP inhibition alone and in combination with cyclosporine significantly prolonged graft survival. Acute rejection led to a typical sequence of initial endothelial dysfunction and reduced contractile reserve followed by progressive systolic and diastolic dysfunction, which were reduced by PARP inhibition. PARP inhibition led to reduced antigen-specific and non-specific proliferation in stimulated T cells and dose-dependently inhibited intracellular adhesion molecule-1 (ICAM-1) up-regulation in stimulated endothelial cells. Conclusions: PARP inhibition was found to prolong graft survival and improve cardiac function during acute cardiac rejection. Direct immunosuppressive properties contribute at least partially to the beneficial effects of PARP inhibitors in graft rejection.

Original languageEnglish (US)
Pages (from-to)794-804
Number of pages11
JournalJournal of Heart and Lung Transplantation
Volume25
Issue number7
DOIs
StatePublished - Jul 2006
Externally publishedYes

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Poly(ADP-ribose) Polymerases
Cyclosporine
Graft Survival
Immunosuppressive Agents
Endothelial Cells
T-Lymphocytes
Transplants
Peroxynitrous Acid
Graft Rejection
Immunologic Factors
Allografts
Up-Regulation
Transplantation
Placebos
Antigens
INO 1001

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Transplantation

Cite this

Immunomodulatory Effects of Poly(ADP-ribose) Polymerase Inhibition Contribute to Improved Cardiac Function and Survival During Acute Cardiac Rejection. / Szabó, Gábor; Bährle, Susanne; Sivanandam, Vijayshankar; Stumpf, Nicole; Gerö, Domokos; Berger, Irina; Beller, Carsten; Hagl, Siegfried; Szabo, Csaba; Dengler, Thomas J.

In: Journal of Heart and Lung Transplantation, Vol. 25, No. 7, 07.2006, p. 794-804.

Research output: Contribution to journalArticle

Szabó, Gábor ; Bährle, Susanne ; Sivanandam, Vijayshankar ; Stumpf, Nicole ; Gerö, Domokos ; Berger, Irina ; Beller, Carsten ; Hagl, Siegfried ; Szabo, Csaba ; Dengler, Thomas J. / Immunomodulatory Effects of Poly(ADP-ribose) Polymerase Inhibition Contribute to Improved Cardiac Function and Survival During Acute Cardiac Rejection. In: Journal of Heart and Lung Transplantation. 2006 ; Vol. 25, No. 7. pp. 794-804.
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AU - Bährle, Susanne

AU - Sivanandam, Vijayshankar

AU - Stumpf, Nicole

AU - Gerö, Domokos

AU - Berger, Irina

AU - Beller, Carsten

AU - Hagl, Siegfried

AU - Szabo, Csaba

AU - Dengler, Thomas J.

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AB - Background: Recent studies have suggested that the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway is activated during acute allograft rejection. Therefore, we investigated whether PARP inhibition improves transplant outcome and the extent to which immunologic factors contribute to the effects of PARP inhibition. Methods: Isogeneic Lewis-to-Lewis and allogeneic Dark Agouti (DA)-to-Lewis rat cardiac transplants were studied under treatment with placebo, the PARP inhibitor INO-1001 (1 mg/kg/day), cyclosporine (2.5 or 5 mg/kg/day) or the combination of INO-1001 and low-dose cyclosporine. Functional, biochemical and histologic analyses were performed 3 and 5 days after transplantation in control and INO-1001-treated animals. In addition, stimulated T cells and endothelial cells were treated with INO-1001 to evaluate the potential immunosuppressive effects of PARP inhibition. Results: PARP inhibition alone and in combination with cyclosporine significantly prolonged graft survival. Acute rejection led to a typical sequence of initial endothelial dysfunction and reduced contractile reserve followed by progressive systolic and diastolic dysfunction, which were reduced by PARP inhibition. PARP inhibition led to reduced antigen-specific and non-specific proliferation in stimulated T cells and dose-dependently inhibited intracellular adhesion molecule-1 (ICAM-1) up-regulation in stimulated endothelial cells. Conclusions: PARP inhibition was found to prolong graft survival and improve cardiac function during acute cardiac rejection. Direct immunosuppressive properties contribute at least partially to the beneficial effects of PARP inhibitors in graft rejection.

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