Heart Transplant Research Today is a free monthly online journal that collates and summarizes the latest research about Heart Transplant, including details on risks, prognosis, procedure, surgery, organ donation.

Immunomodulatory effects of poly(ADP-ribose) polymerase inhibition contribute to improved cardiac function and survival during acute cardiac rejection.

Szabó G, Bährle S, Sivanandam V, Stumpf N, Gerö D, Berger I, Beller C, Hagl S, Szabó C, Dengler TJ

Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. dzsi@hotmail.com

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.

Published 4 July 2006 in J Heart Lung Transplant, 25(7): 794-804.
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