Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

Authors

  • Lucia Russo,

    1. Hepatic Hemodynamic Lab, Liver Unit, IMDIM, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain
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    • These authors contributed equally to this work.

  • Jorge Gracia-Sancho,

    Corresponding author
    1. Hepatic Hemodynamic Lab, Liver Unit, IMDIM, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain
    • Hepatic Hemodynamic Laboratory, Hospital Clínic de Barcelona, IDIBAPS, Esther Koplowitz Centre, Rosselló 149, Room 4.5, 08036 Barcelona, Spain
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    • These authors contributed equally to this work.

  • Héctor García-Calderó,

    1. Hepatic Hemodynamic Lab, Liver Unit, IMDIM, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain
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  • Giusi Marrone,

    1. Hepatic Hemodynamic Lab, Liver Unit, IMDIM, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain
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  • Juan Carlos García-Pagán,

    1. Hepatic Hemodynamic Lab, Liver Unit, IMDIM, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain
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  • Guillermo García-Cardeña,

    1. Center for Excellence in Vascular Biology, Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
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  • Jaime Bosch

    Corresponding author
    1. Hepatic Hemodynamic Lab, Liver Unit, IMDIM, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain
    • Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic i Provincial, Villarroel 170, 08036 Barcelona, Spain
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    • Fax: +34932279856


  • Potential conflict of interest: Nothing to report.

  • Supported by grants from the Instituto de Salud Carlos III (PS 09/01261 to J.B. and FIS 11/00235 to J.G.-S.) and Ministerio de Ciencia e Innovación (SAF 2010/17043 to J.C.G.-P.). G.M. is a recipient of a fellowship from Instituto de Salud Carlos III (PFIS 09/00540), and J.G.-S. of a contract from the Programa Ramón y Cajal, Ministerio de Ciencia e Innovacion, Spain. Ciberehd is funded by Instituto de Salud Carlos III.

Abstract

Pathophysiological alterations in the endothelial phenotype result in endothelial dysfunction. Flow cessation, occurring during organ procurement for transplantation, triggers the endothelial dysfunction characteristic of ischemia/reperfusion injury, partly due to a reduction in the expression of the vasoprotective transcription factor Kruppel-like Factor 2 (KLF2). We aimed at (1) characterizing the effects of flow cessation and cold storage on hepatic endothelial phenotype, and (2) ascertaining if the consequences of cold stasis on the hepatic endothelium can be pharmacologically modulated, improving liver graft function. Expression of KLF2 and its vasoprotective programs was determined in (i) hepatic endothelial cells (HEC) incubated under cold storage conditions with or without the KLF2-inducer simvastatin, and (ii) rat livers not cold stored or preserved in cold University of Wisconsin solution (UWS) supplemented with simvastatin or its vehicle. In addition, upon warm reperfusion hepatic vascular resistance, endothelial function, nitric oxide vasodilator pathway, apoptosis, inflammation, and liver injury were evaluated in not cold stored livers or livers preserved in cold UWS supplemented with simvastatin or vehicle. Expression of KLF2 and its vasoprotective programs decrease in HEC incubated under cold storage conditions. Cold-stored rat livers exhibit a time-dependent decrease in KLF2 and its target genes, liver injury, increased hepatic vascular resistance, and endothelial dysfunction. The addition of simvastatin to the storage solution, maintained KLF2-dependent vasoprotective programs, prevented liver damage, inflammation, and oxidative stress and improved endothelial dysfunction. Conclusion: Our results provide a rationale to evaluate the beneficial effects of a vasoprotective preservation solution on human liver procurement for transplantation. (Hepatology 2012)

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