Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation

Gábor Szabó; Susanne Bährle; Nicole Stumpf; Karin Sonnenberg; Éva Szabó; Pál Pacher; Tamás Csont; Richard Schulz; Thomas J. Dengler; Lucas Liaudet; Prakash G. Jagtap; Garry J. Southan; Christian F. Vahl; Siegfried Hagl; Csaba Szabó

doi:10.1161/hh0102.102657

Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation

Gábor Szabó, Susanne Bährle, Nicole Stumpf, Karin Sonnenberg, Éva Szabó, Pál Pacher, Tamás Csont, Richard Schulz, Thomas J. Dengler, Lucas Liaudet, Prakash G. Jagtap, Garry J. Southan, Christian F. Vahl, Siegfried Hagl, Csaba Szabó

Research output: Contribution to journal › Article

144 Scopus citations

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	https://doi.org/10.1161/hh0102.102657
State	Published - Jan 11 2002

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Keywords

Endothelial function
PARP inhibition
Rat
Reperfusion injury
Transplantation

ASJC Scopus subject areas

Physiology
Cardiology and Cardiovascular Medicine

Cite this

Szabó, G., Bährle, S., Stumpf, N., Sonnenberg, K., Szabó, É., Pacher, P., Csont, T., Schulz, R., Dengler, T. J., Liaudet, L., Jagtap, P. G., Southan, G. J., Vahl, C. F., Hagl, S., & Szabó, C. (2002). Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation. Circulation Research, 90(1), 100-106. https://doi.org/10.1161/hh0102.102657

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; Szabó, Csaba.

In: Circulation Research, Vol. 90, No. 1, 11.01.2002, p. 100-106.

Research output: Contribution to journal › Article

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 ; Szabó, Csaba. / Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation. In: Circulation Research. 2002 ; Vol. 90, No. 1. pp. 100-106.

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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.",

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AU - Pacher, Pál

AU - Csont, Tamás

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AU - Dengler, Thomas J.

AU - Liaudet, Lucas

AU - Jagtap, Prakash G.

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10.1161/hh0102.102657