Prolonging hypothermic ischaemic cardiac and vascular storage by inhibiting the activation of the nuclear enzyme poly(adenosine diphosphate-ribose) polymerase

Sevil Korkmaz-Icöz, Tamás Radovits, Sivakkanan Loganathan, Shiliang Li, Mihály Ruppert, Kálmán Benke, Paige Brlecic, Csaba Szabo, Matthias Karck, Gábor Szabó

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    Abstract

    limiting factor. Striving to optimize the use of this limited resource, the aspect that long distance procurement may increase the available donor pool must be taken into consideration. As poly(ADP-ribose)polymerase (PARP)-activation has been identified as a key pathway of reperfusion injury, we assessed the hypothesis that its inhibition would allow an extension of cold preservation time and protect the graft against ischaemia/reperfusion injury. METHODS: Hearts from donor rats were explanted, stored in a preservation solution (Custodiol) at 4 °C for 4 h or 8 h, and heterotopically transplanted. A vehicle or the PARP-inhibitor, INO-1001 (5 mg/kg), was administered during the reperfusion period. We evaluated posttransplant graft function with a Millar micromanometer at different left-ventricular volumes. Additionally, in organ bath experiments the effect of PARP-inhibition on endothelium-dependent and -independent vasorelaxation was evaluated after long-term cold ischaemic storage/warm reperfusion. RESULTS: PARP-inhibition resulted in a better systolic functional recovery of grafts submitted to 4 h and 8 h ischaemia. Furthermore, INO- 1001 decreased the left-ventricular end-diastolic pressure after 8 h of ischaemia. Coronary blood flow was significantly higher after PARPinhibition in comparison to controls. Endothelium-dependent vasorelaxation was significantly better in the INO-1001-groups than in the vehicle-treated transplant groups. After 24-h hypothermic storage, treatment of aortic ring with INO-1001 during reoxygenation significantly improved endothelial dysfunction. CONCLUSIONS: By inhibiting the PARP activation, INO-1001 can protect the graft and endothelium from the injury that is caused by prolonged cold myocardial ischaemia/reperfusion, thereby improving post-transplant graft function.

    Original languageEnglish (US)
    Article numberezw426
    Pages (from-to)829-835
    Number of pages7
    JournalEuropean Journal of Cardio-thoracic Surgery
    Volume51
    Issue number5
    DOIs
    StatePublished - May 1 2017

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    Keywords

    • Endothelial dysfunction
    • Heart transplantation
    • Poly(ADP-ribose) polymerase

    ASJC Scopus subject areas

    • Surgery
    • Pulmonary and Respiratory Medicine
    • Cardiology and Cardiovascular Medicine

    Cite this

    Korkmaz-Icöz, S., Radovits, T., Loganathan, S., Li, S., Ruppert, M., Benke, K., Brlecic, P., Szabo, C., Karck, M., & Szabó, G. (2017). Prolonging hypothermic ischaemic cardiac and vascular storage by inhibiting the activation of the nuclear enzyme poly(adenosine diphosphate-ribose) polymerase. European Journal of Cardio-thoracic Surgery, 51(5), 829-835. [ezw426]. https://doi.org/10.1093/ejcts/ezw426