Inhibition of poly-ADP ribose synthase (PARS) increases cardiac myocyte survival during acute cardiac allograft rejection in rats

Abstract

Death of cardiomyocytes by apoptosis and by necrosis is a hallmark of acute cardiac allograft rejection. Studies of cardiac myoblasts and cardiac myocytes in culture indicated that activation of poly ADP ribose synthase (PARS) by agonists such as NO, peroxynitrite and TNFalpha contribute to both forms of cardiac muscle cell death. To investigate the role of PARS activation in acute allograft rejection Lewis-Wistar-Furth heterotopic abdominal heart transplantation was performed in rats. In animals treated with the PARS inhibitor 5-aminoisoquinolinone (5AIQ) (3 mg/kg i.p. bid) cardiac allograft survival was prolonged from 6 ± 2 to 10 ± 1.7 days (n=6, n=8 diff p<0.02). At day 5 following transplantation PARS mRNA, protein and poly ADP ribose protein were increased in the allografts of both groups. Myocyte damage determined by the TUNEL technique and immunoperoxidase staining for soluble fibronectin was reduced by 66% from 16.7 to 5.7 damaged myocytes per mm2 myocardium in vehicle vs. 5AIQ treated allografts. Myocardial inflammation was also reduced by 49% for ED1+ macrophages, 34% for CD3+ lymphocytes and 51% for NOS-2+ inflammatory cells.