Immunomodulatory effects of poly(ADP-ribose) polymerase inhibition contribute to improved cardiac function and survival during acute cardiac rejection.
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.
Szabó
Gábor
G
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. dzsi@hotmail.com
Bährle
Susanne
S
Sivanandam
Vijayshankar
V
Stumpf
Nicole
N
Gerö
Domokos
D
Berger
Irina
I
Beller
Carsten
C
Hagl
Siegfried
S
Szabó
Csaba
C
Dengler
Thomas J
TJ
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000503:physiopathology; D004280:Dobutamine / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006085:Graft Survival; D006321:Heart / Q000503:physiopathology*; D016027:Heart Transplantation; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008213:Lymphocyte Activation; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010710:Phosphates / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D002316:Cardiotonic Agents; C491685:INO 1001; D007211:Indoles; D010710:Phosphates; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004280:Dobutamine