Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 100-106 |
| Number of pages | 7 |
| Journal | Circulation Research |
| Volume | 90 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 11 2002 |
| Externally published | Yes |
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Keywords
- Endothelial function
- PARP inhibition
- Rat
- Reperfusion injury
- Transplantation
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation. / Szabó, Gábor; Bährle, Susanne; Stumpf, Nicole; Sonnenberg, Karin; Szabó, Éva; Pacher, Pál; Csont, Tamás; Schulz, Richard; Dengler, Thomas J.; Liaudet, Lucas; Jagtap, Prakash G.; Southan, Garry J.; Vahl, Christian F.; Hagl, Siegfried; Szabo, Csaba.
In: Circulation Research, Vol. 90, No. 1, 11.01.2002, p. 100-106.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation
AU - Szabó, Gábor
AU - Bährle, Susanne
AU - Stumpf, Nicole
AU - Sonnenberg, Karin
AU - Szabó, Éva
AU - Pacher, Pál
AU - Csont, Tamás
AU - Schulz, Richard
AU - Dengler, Thomas J.
AU - Liaudet, Lucas
AU - Jagtap, Prakash G.
AU - Southan, Garry J.
AU - Vahl, Christian F.
AU - Hagl, Siegfried
AU - Szabo, Csaba
PY - 2002/1/11
Y1 - 2002/1/11
N2 - 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.
AB - 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.
KW - Endothelial function
KW - PARP inhibition
KW - Rat
KW - Reperfusion injury
KW - Transplantation
UR - http://www.scopus.com/inward/record.url?scp=0037059516&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037059516&partnerID=8YFLogxK
U2 - 10.1161/hh0102.102657
DO - 10.1161/hh0102.102657
M3 - Article
C2 - 11786525
AN - SCOPUS:0037059516
VL - 90
SP - 100
EP - 106
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 1
ER -