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 Szabo

Research output: Contribution to journalArticle

141 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)100-106
Number of pages7
JournalCirculation Research
Volume90
Issue number1
DOIs
StatePublished - Jan 11 2002
Externally publishedYes

Fingerprint

Poly(ADP-ribose) Polymerases
Heart Transplantation
Reperfusion Injury
Reperfusion
Phosphates
Transplants
P-Selectin
Ventricular Pressure
Intercellular Adhesion Molecule-1
Down-Regulation
Ischemia
Placebos
Pharmacology
Staining and Labeling
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Poly(ADP-ribose) Polymerase Inhibitors
Therapeutics

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., ... Szabo, 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; Szabo, Csaba.

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

Research output: Contribution to journalArticle

Szabó, G, Bährle, S, Stumpf, N, Sonnenberg, K, Szabó, É, Pacher, P, Csont, T, Schulz, R, Dengler, TJ, Liaudet, L, Jagtap, PG, Southan, GJ, Vahl, CF, Hagl, S & Szabo, C 2002, 'Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation', Circulation Research, vol. 90, no. 1, pp. 100-106. https://doi.org/10.1161/hh0102.102657
Szabó G, Bährle S, Stumpf N, Sonnenberg K, Szabó É, Pacher P et al. Poly(ADP-ribose) polymerase inhibition reduces reperfusion injury after heart transplantation. Circulation Research. 2002 Jan 11;90(1):100-106. https://doi.org/10.1161/hh0102.102657
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. / 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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