Poly(ADP-ribose) polymerase inhibition attenuates biventricular reperfusion injury after orthotopic heart transplantation

Gábor Szabó, Pál Soós, Ulrike Heger, Christa Flechtenmacher, Susanne Bährle, Zsuzsanna Zsengellér, Csaba Szabo, Siegfried Hagl

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Objective: Poly (ADP-ribose) polymerase (PARP) activation plays a key role in free radical induced injury in ischemia/reperfusion. We investigated the effects of INO-1001 a novel PARP inhibitor on postischemic myocardial and endothelial function. Methods: In dogs, 12 orthotopic heart transplantations were performed after 4 h ischemic preservation. At the beginning of reperfusion either saline vehicle (control, n=6), or INO-1001 (1 mg/kg, n=6) was applied. Before explantation and after 120 min of reperfusion we measured biventricular pressure-volume relationships by a combined conductance catheter and the adaptation potential of the right ventricle to acute afterload increase by pulmonary banding. Coronary blood flow (CBF), vasoreactivity, PARP-activation and ATP-content were also determined. Results: INO-1001 led to significantly better recovery of contractility (91±3 vs. 44±7%, P<0.05) and CBF (44±4 vs. 29±3 ml/min, P<0.05) and higher increase in CBF after acetylcholine (61±10 vs. 27±8%, P<0.05). In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved after INO-1001. ATP content was significantly higher in the INO-1001 group (11.0±2.1 vs. 4.5±1.1 μmol/g drw). Immunhistology revealed PARP activation in the control group which was abolished by INO-1001 treatment. Conclusions: PARP inhibition reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation.

Original languageEnglish (US)
Pages (from-to)226-234
Number of pages9
JournalEuropean Journal of Cardio-thoracic Surgery
Volume27
Issue number2
DOIs
StatePublished - Feb 2005
Externally publishedYes

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Poly(ADP-ribose) Polymerases
Heart Transplantation
Reperfusion Injury
Reperfusion
Heart Ventricles
Adenosine Triphosphate
Myocardial Reperfusion Injury
Acetylcholine
Free Radicals
INO 1001
Catheters
Dogs
Pressure
Lung
Control Groups

Keywords

  • Heart transplantation
  • PARP
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Poly(ADP-ribose) polymerase inhibition attenuates biventricular reperfusion injury after orthotopic heart transplantation. / Szabó, Gábor; Soós, Pál; Heger, Ulrike; Flechtenmacher, Christa; Bährle, Susanne; Zsengellér, Zsuzsanna; Szabo, Csaba; Hagl, Siegfried.

In: European Journal of Cardio-thoracic Surgery, Vol. 27, No. 2, 02.2005, p. 226-234.

Research output: Contribution to journalArticle

Szabó, Gábor ; Soós, Pál ; Heger, Ulrike ; Flechtenmacher, Christa ; Bährle, Susanne ; Zsengellér, Zsuzsanna ; Szabo, Csaba ; Hagl, Siegfried. / Poly(ADP-ribose) polymerase inhibition attenuates biventricular reperfusion injury after orthotopic heart transplantation. In: European Journal of Cardio-thoracic Surgery. 2005 ; Vol. 27, No. 2. pp. 226-234.
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AU - Szabó, Gábor

AU - Soós, Pál

AU - Heger, Ulrike

AU - Flechtenmacher, Christa

AU - Bährle, Susanne

AU - Zsengellér, Zsuzsanna

AU - Szabo, Csaba

AU - Hagl, Siegfried

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N2 - Objective: Poly (ADP-ribose) polymerase (PARP) activation plays a key role in free radical induced injury in ischemia/reperfusion. We investigated the effects of INO-1001 a novel PARP inhibitor on postischemic myocardial and endothelial function. Methods: In dogs, 12 orthotopic heart transplantations were performed after 4 h ischemic preservation. At the beginning of reperfusion either saline vehicle (control, n=6), or INO-1001 (1 mg/kg, n=6) was applied. Before explantation and after 120 min of reperfusion we measured biventricular pressure-volume relationships by a combined conductance catheter and the adaptation potential of the right ventricle to acute afterload increase by pulmonary banding. Coronary blood flow (CBF), vasoreactivity, PARP-activation and ATP-content were also determined. Results: INO-1001 led to significantly better recovery of contractility (91±3 vs. 44±7%, P<0.05) and CBF (44±4 vs. 29±3 ml/min, P<0.05) and higher increase in CBF after acetylcholine (61±10 vs. 27±8%, P<0.05). In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved after INO-1001. ATP content was significantly higher in the INO-1001 group (11.0±2.1 vs. 4.5±1.1 μmol/g drw). Immunhistology revealed PARP activation in the control group which was abolished by INO-1001 treatment. Conclusions: PARP inhibition reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation.

AB - Objective: Poly (ADP-ribose) polymerase (PARP) activation plays a key role in free radical induced injury in ischemia/reperfusion. We investigated the effects of INO-1001 a novel PARP inhibitor on postischemic myocardial and endothelial function. Methods: In dogs, 12 orthotopic heart transplantations were performed after 4 h ischemic preservation. At the beginning of reperfusion either saline vehicle (control, n=6), or INO-1001 (1 mg/kg, n=6) was applied. Before explantation and after 120 min of reperfusion we measured biventricular pressure-volume relationships by a combined conductance catheter and the adaptation potential of the right ventricle to acute afterload increase by pulmonary banding. Coronary blood flow (CBF), vasoreactivity, PARP-activation and ATP-content were also determined. Results: INO-1001 led to significantly better recovery of contractility (91±3 vs. 44±7%, P<0.05) and CBF (44±4 vs. 29±3 ml/min, P<0.05) and higher increase in CBF after acetylcholine (61±10 vs. 27±8%, P<0.05). In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved after INO-1001. ATP content was significantly higher in the INO-1001 group (11.0±2.1 vs. 4.5±1.1 μmol/g drw). Immunhistology revealed PARP activation in the control group which was abolished by INO-1001 treatment. Conclusions: PARP inhibition reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation.

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