title: Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy.
abstract: Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized the microcirculatory status and endothelial phenotype of livers undergoing WIR, and evaluated the use of simvastatin in WIR injury prevention. Male Wistar rats received simvastatin, or vehicle, 30 min before undergoing 60 min of partial warm ischemia (70%) followed by 2 h or 24 h of reperfusion. Hepatic and systemic hemodynamics, liver injury (AST, ALT, LDH), endothelial function (vasodilatation in response to acetylcholine), KLF2 and nitric oxide pathways, oxidative stress, inflammation (neutrophil and macrophage infiltration) and cell death were evaluated. Profound microcirculatory dysfunction occurred rapidly following WIR. This was evidenced by down-regulation of the KLF2 vasoprotective pathway, impaired vasodilatory capability and endothelial activation, altogether leading to increased hepatic vascular resistance and liver inflammation, with significant leukocyte infiltration, oxidative stress and cell death. Simvastatin preserved the hepatic endothelial phenotype, and blunted the detrimental effects of WIR on liver hemodynamics and organ integrity. In conclusion, WIR-induced injury to liver sinusoidal endothelial cells is mitigated by pre-treatment with Simvastatin probably through a KLF2-dependent mechanism.
authors.affiliation: Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute - Hospital Clinic de Barcelona - CIBEREHD. Barcelona, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Hide
authors.affiliation: Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute - Hospital Clinic de Barcelona - CIBEREHD. Barcelona, Spain.
authors.forename: Martí
authors.initials: M
authors.lastname: Ortega-Ribera
authors.affiliation: Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute - Hospital Clinic de Barcelona - CIBEREHD. Barcelona, Spain.
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Garcia-Pagan
authors.affiliation: IDIBAPS &CIBEREHD.
authors.forename: Carmen
authors.initials: C
authors.lastname: Peralta
authors.affiliation: Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute - Hospital Clinic de Barcelona - CIBEREHD. Barcelona, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.affiliation: Barcelona Hepatic Hemodynamic Lab. IDIBAPS Biomedical Research Institute - Hospital Clinic de Barcelona - CIBEREHD. Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Gracia-Sancho
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008833:Microcirculation; D020556:Neutrophil Infiltration; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D052096:Warm Ischemia / Q000009:adverse effects*
chemical_list: C543921:Klf2 protein, rat; D051741:Kruppel-Like Transcription Factors; D009569:Nitric Oxide; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat