Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy

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...

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Authors: Hide Alférez, Diana, Ortega Ribera, Martí, García Pagán, Juan Carlos, Peralta Uroz, Carmen, Bosch i Genover, Jaume, Gracia-Sancho, Jorge
Format: article
Status:Published version
Publication Date:2016
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/118684
Online Access:https://hdl.handle.net/2445/118684
Access Level:Open access
Keyword:Isquèmia
Reperfusió (Fisiologia)
Agents antilipèmics
Microcirculació
Fetge
Ischemia
Reperfusion (Physiology)
Antilipemic agents
Microcirculation
Liver
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spelling Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapyHide Alférez, DianaOrtega Ribera, MartíGarcía Pagán, Juan CarlosPeralta Uroz, CarmenBosch i Genover, JaumeGracia-Sancho, JorgeIsquèmiaReperfusió (Fisiologia)Agents antilipèmicsMicrocirculacióFetgeIschemiaReperfusion (Physiology)Antilipemic agentsMicrocirculationLiverWarm 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.Nature Publishing Group2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/118684Articles publicats en revistes (Medicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/srep22107Scientific Reports, 2016, vol. 6, p. 22107https://doi.org/10.1038/srep22107cc-by (c) Hide Alférez, Diana et al., 2016http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1186842026-05-27T06:46:51Z
dc.title.none.fl_str_mv Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy
title Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy
spellingShingle Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy
Hide Alférez, Diana
Isquèmia
Reperfusió (Fisiologia)
Agents antilipèmics
Microcirculació
Fetge
Ischemia
Reperfusion (Physiology)
Antilipemic agents
Microcirculation
Liver
title_short Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy
title_full Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy
title_fullStr Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy
title_full_unstemmed Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy
title_sort Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy
dc.creator.none.fl_str_mv Hide Alférez, Diana
Ortega Ribera, Martí
García Pagán, Juan Carlos
Peralta Uroz, Carmen
Bosch i Genover, Jaume
Gracia-Sancho, Jorge
author Hide Alférez, Diana
author_facet Hide Alférez, Diana
Ortega Ribera, Martí
García Pagán, Juan Carlos
Peralta Uroz, Carmen
Bosch i Genover, Jaume
Gracia-Sancho, Jorge
author_role author
author2 Ortega Ribera, Martí
García Pagán, Juan Carlos
Peralta Uroz, Carmen
Bosch i Genover, Jaume
Gracia-Sancho, Jorge
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Isquèmia
Reperfusió (Fisiologia)
Agents antilipèmics
Microcirculació
Fetge
Ischemia
Reperfusion (Physiology)
Antilipemic agents
Microcirculation
Liver
topic Isquèmia
Reperfusió (Fisiologia)
Agents antilipèmics
Microcirculació
Fetge
Ischemia
Reperfusion (Physiology)
Antilipemic agents
Microcirculation
Liver
description 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.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/118684
url https://hdl.handle.net/2445/118684
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/srep22107
Scientific Reports, 2016, vol. 6, p. 22107
https://doi.org/10.1038/srep22107
dc.rights.none.fl_str_mv cc-by (c) Hide Alférez, Diana et al., 2016
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Hide Alférez, Diana et al., 2016
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869415932721364992
score 15,301603

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