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Immunomodulatory effects of poly(ADP-ribose) polymerase inhibition contribute to improved cardiac function and survival during acute cardiac rejection
- Source :
- The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 25(7)
- Publication Year :
- 2005
-
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.
- Subjects :
- Pulmonary and Respiratory Medicine
Cardiac function curve
Graft Rejection
Cardiotonic Agents
Indoles
Poly ADP ribose polymerase
T-Lymphocytes
Diastole
Pharmacology
Poly(ADP-ribose) Polymerase Inhibitors
Lymphocyte Activation
Phosphates
chemistry.chemical_compound
Dobutamine
Ribose
Medicine
Animals
Humans
Transplantation, Homologous
Endothelial dysfunction
Cells, Cultured
Transplantation
business.industry
Myocardium
Graft Survival
Hemodynamics
Endothelial Cells
Heart
Rats, Inbred Strains
medicine.disease
Coronary Vessels
Rats
Transplantation, Isogeneic
chemistry
Rats, Inbred Lew
Immune System
PARP inhibitor
Immunology
Heart Transplantation
Surgery
Cardiology and Cardiovascular Medicine
business
Intracellular
Subjects
Details
- ISSN :
- 15573117
- Volume :
- 25
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
- Accession number :
- edsair.doi.dedup.....044b420d0afe0cf451688c2cde76dff2