Published online before print November 26, 2001, doi: 10.1161/hh0102.102657
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Submitted on July 3, 2001
Revised on November 6, 2001
Accepted on November 13, 2001
Poly(ADP-Ribose) Polymerase Inhibition Reduces Reperfusion Injury After Heart Transplantation
From the Departments of Cardiac Surgery (G.S., N.S., K.S., C.F.V., S.H.) and Cardiology (S.B., T.J.D.), University of Heidelberg, Germany; Inotek Corporation (E.S., P.P., L.L., G.J.S., C.S.), Beverly, Mass; and the Cardiovascular Research Group, Department of Pharmacology (T.C., R.S.), Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada.
* To whom correspondence should be addressed. E-mail: dzsi{at}hotmail.com.
The aim of the present study was to investigate the effects of the novel poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide) on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After a 1-hour ischemic preservation, reperfusion was started either after application of placebo or PJ34 (3 mg/kg). The assessment of left ventricular pressure--volume relations, total coronary blood flow, endothelial function, myocardial high energy phosphates, and histological analysis were performed at 1 and 24 hours of reperfusion. After 1 hour, myocardial contractility and relaxation, coronary blood flow, and endothelial function were significantly improved and myocardial high energy phosphate content was preserved in the PJ34-treated animals. Improved transplant function was also seen with treatment with another, structurally different PARP inhibitor, 5-aminoisoquinoline. The PARP inhibitors did not affect baseline cardiac function. Immunohistological staining confirmed that PJ34 prevented the activation of PARP in the transplanted hearts. The activation of P-selectin and ICAM-1 was significantly elevated in the vehicle-treated heart transplantation group. Thus, pharmacological PARP inhibition reduces reperfusion injury after heart transplantation due to prevention of energy depletion and downregulation of adhesion molecules and exerts a beneficial effect against reperfusion-induced graft coronary endothelial dysfunction.
Key words: transplantation • reperfusion injury • PARP inhibition • endothelial function • rat
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