Published online before print November 26, 2001, doi: 10.1161/hh0102.102657
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© 2002 American Heart Association, Inc.
Integrative Physiology |
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.
Correspondence to Gábor Szabó, MD, PhD, Department of Cardiac Surgery, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany. 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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