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


CONCLUSIONS
Our results provide a rationale to evaluate the beneficial effects of a vasoprotective preservation solution on human liver procurement for transplantation.
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.
Lucia
L
Russo
Jorge
J
Gracia-Sancho
Héctor
H
García-Calderó
Giusi
G
Marrone
Juan Carlos
JC
García-Pagán
Guillermo
G
García-Cardeña
Jaime
J
Bosch
D000241:Adenosine / Q000494:pharmacology / Q000627:therapeutic use; D000493:Allopurinol / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D003451:Cryoprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005978:Glutathione / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology; D016031:Liver Transplantation / Q000379:methods; D008297:Male; D023421:Models, Animal; D009926:Organ Preservation / Q000379:methods; D019188:Organ Preservation Solutions / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D011887:Raffinose / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*
D003451:Cryoprotective Agents; D007328:Insulin; C543921:Klf2 protein, rat; D051741:Kruppel-Like Transcription Factors; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D019821:Simvastatin; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose