Poly(ADP-Ribose) polymerase inhibition reduces reperfusion injury after heart transplantation.
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.
Szabó
Gábor
G
Department of Cardiac Surgery, University of Heidelberg, Germany. dzsi@hotmail.com
Bährle
Susanne
S
Stumpf
Nicole
N
Sonnenberg
Karin
K
Szabó E
Eva
E
Pacher
Pál
P
Csont
Tamás
T
Schulz
Richard
R
Dengler
Thomas J
TJ
Liaudet
Lucas
L
Jagtap
Prakash G
PG
Southan
Garry J
GJ
Vahl
Christian F
CF
Hagl
Siegfried
S
Szabó
Csaba
C
D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003326:Coronary Circulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D016027:Heart Transplantation; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D019007:P-Selectin / Q000032:analysis; D010616:Phenanthrenes / Q000494:pharmacology*; D010725:Phosphocreatine / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D019007:P-Selectin; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D010725:Phosphocreatine; D018799:Intercellular Adhesion Molecule-1; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases