Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH

Ambrisentan; Endotelina-1; Cèl·lules estelades hepàtiques

Detalhes bibliográficos
Autores: Bravo Garmendia, Miren, Raurell Saborit, Immaculada, Barbera Belles, Aurora, Hide Alferez, Diana, Estrella Gonzalez, Federico, Salcedo Allende, Maria Teresa, Genescà Ferrer, Joan, Gil Soler, Mar, Martell Pérez-Alcalde, Maria, Augustin Recio, Salvador
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Departament de Salut de la Generalitat de Catalunya (DS)
Repositorio:Scientia. Dipòsit d'Informació Digital del Departament de Salut
OAI Identifier:oai:scientiasalut.gencat.cat:11351/6765
Acesso em linha:https://hdl.handle.net/11351/6765
Access Level:acceso abierto
Palavra-chave:Fetge - Malalties - Tractament
Rates
DISEASES::Digestive System Diseases::Liver Diseases
Other subheadings::Other subheadings::Other subheadings::/drug therapy
ORGANISMS::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::Rats
ENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticas
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
ORGANISMOS::Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratas
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oai_identifier_str oai:scientiasalut.gencat.cat:11351/6765
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH
title Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH
spellingShingle Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH
Bravo Garmendia, Miren
Fetge - Malalties - Tractament
Rates
DISEASES::Digestive System Diseases::Liver Diseases
Other subheadings::Other subheadings::Other subheadings::/drug therapy
ORGANISMS::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::Rats
ENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticas
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
ORGANISMOS::Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratas
title_short Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH
title_full Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH
title_fullStr Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH
title_full_unstemmed Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH
title_sort Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH
dc.creator.none.fl_str_mv Bravo Garmendia, Miren
Raurell Saborit, Immaculada
Barbera Belles, Aurora
Hide Alferez, Diana
Estrella Gonzalez, Federico
Salcedo Allende, Maria Teresa
Genescà Ferrer, Joan
Gil Soler, Mar
Martell Pérez-Alcalde, Maria
Augustin Recio, Salvador
author Bravo Garmendia, Miren
author_facet Bravo Garmendia, Miren
Raurell Saborit, Immaculada
Barbera Belles, Aurora
Hide Alferez, Diana
Estrella Gonzalez, Federico
Salcedo Allende, Maria Teresa
Genescà Ferrer, Joan
Gil Soler, Mar
Martell Pérez-Alcalde, Maria
Augustin Recio, Salvador
author_role author
author2 Raurell Saborit, Immaculada
Barbera Belles, Aurora
Hide Alferez, Diana
Estrella Gonzalez, Federico
Salcedo Allende, Maria Teresa
Genescà Ferrer, Joan
Gil Soler, Mar
Martell Pérez-Alcalde, Maria
Augustin Recio, Salvador
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Institut Català de la Salut
[Bravo M, Barberá A, Gil M, Estrella F] Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Raurell I, Hide D, Augustin S, Genescà J, Martell M] Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain. [Salcedo MT] Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
dc.subject.none.fl_str_mv Fetge - Malalties - Tractament
Rates
DISEASES::Digestive System Diseases::Liver Diseases
Other subheadings::Other subheadings::Other subheadings::/drug therapy
ORGANISMS::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::Rats
ENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticas
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
ORGANISMOS::Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratas
topic Fetge - Malalties - Tractament
Rates
DISEASES::Digestive System Diseases::Liver Diseases
Other subheadings::Other subheadings::Other subheadings::/drug therapy
ORGANISMS::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::Rats
ENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticas
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
ORGANISMOS::Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratas
description Ambrisentan; Endotelina-1; Cèl·lules estelades hepàtiques
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
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/11351/6765
url https://hdl.handle.net/11351/6765
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Disease Models & Mechanisms;14(5)
https://doi.org/10.1242/dmm.048884
info:eu-repo/grantAgreement/ES/PE2013-2016/PI18%2F00947
info:eu-repo/grantAgreement/ES/PE2013-2016/PI17%2F00754
info:eu-repo/grantAgreement/ES/PE2013-2016/AC18%2F00033
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Company Biologists
publisher.none.fl_str_mv Company Biologists
dc.source.none.fl_str_mv Scientia
reponame:Scientia. Dipòsit d'Informació Digital del Departament de Salut
instname:Departament de Salut de la Generalitat de Catalunya (DS)
instname_str Departament de Salut de la Generalitat de Catalunya (DS)
reponame_str Scientia. Dipòsit d'Informació Digital del Departament de Salut
collection Scientia. Dipòsit d'Informació Digital del Departament de Salut
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869418196512014336
spelling Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASHBravo Garmendia, MirenRaurell Saborit, ImmaculadaBarbera Belles, AuroraHide Alferez, DianaEstrella Gonzalez, FedericoSalcedo Allende, Maria TeresaGenescà Ferrer, JoanGil Soler, MarMartell Pérez-Alcalde, MariaAugustin Recio, SalvadorFetge - Malalties - TractamentRatesDISEASES::Digestive System Diseases::Liver DiseasesOther subheadings::Other subheadings::Other subheadings::/drug therapyORGANISMS::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::RatsENFERMEDADES::enfermedades del sistema digestivo::enfermedades hepáticasOtros calificadores::Otros calificadores::Otros calificadores::/farmacoterapiaORGANISMOS::Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratasAmbrisentan; Endotelina-1; Cèl·lules estelades hepàtiquesAmbrisentan; Endotelina-1; Células estrelladas hepáticasAmbrisentan; Endothelin-1; Hepatic stellate cellsIn non-alcoholic steatohepatitis (NASH), decreased nitric oxide and increased endothelin-1 (ET-1, also known as EDN1) released by sinusoidal endothelial cells (LSEC) induce hepatic stellate cell (HSC) contraction and contribute to portal hypertension (PH). Statins improve LSEC function, and ambrisentan is a selective endothelin-receptor-A antagonist. We aimed to analyse the combined effects of atorvastatin and ambrisentan on liver histopathology and hemodynamics, together with assessing the underlying mechanism in a rat NASH model. Diet-induced NASH rats were treated with atorvastatin (10 mg/kg/day), ambrisentan (30 mg/kg/day or 2 mg/kg/day) or a combination of both for 2 weeks. Hemodynamic parameters were registered and liver histology and serum biochemical determinations analysed. Expression of proteins were studied by immunoblotting. Conditioned media experiments were performed with LSEC. HSCs were characterized by RT-PCR, and a collagen lattice contraction assay was performed. Atorvastatin and ambrisentan act synergistically in combination to completely normalize liver hemodynamics and reverse histological NASH by 75%. Atorvastatin reversed the sinusoidal contractile phenotype, thus improving endothelial function, whereas ambrisentan prevented the contractile response in HSCs by blocking ET-1 response. Additionally, ambrisentan also increased eNOS (also known as Nos3) phosphorylation levels in LSEC, via facilitating the stimulation of endothelin-receptor-B in these cells. Furthermore, the serum alanine aminotransferase of the combined treatment group decreased to normal levels, and this group exhibited a restoration of the HSC quiescent phenotype. The combination of atorvastatin and ambrisentan remarkably improves liver histology and PH in a diet-induced NASH model. By recovering LSEC function, together with inhibiting the activation and contraction of HSC, this combined treatment may be an effective treatment for NASH patients.This work was supported by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (European Regional Development Fund/European Social Fund, ‘Investing in your future’) [PI17/00310 to S.A., PI17/00754 to M.M., and PI18/00947 and AC18/00033 (ENM3 2018) to J.G.]. J.G. is a recipient of a clinical intensification award and D.H. is a recipient of a Sara Borrell grant (both from ISCIII). M.G. and A.B. have predoctoral fellowships from the Agència de Gestió d'Ajuts Universitaris i de Recerca and ISCIII, respectively. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is supported by ISCIII.Company BiologistsInstitut Català de la Salut[Bravo M, Barberá A, Gil M, Estrella F] Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Raurell I, Hide D, Augustin S, Genescà J, Martell M] Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain. [Salcedo MT] Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, SpainVall d'Hebron Barcelona Hospital Campus202220222021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11351/6765Scientiareponame:Scientia. Dipòsit d'Informació Digital del Departament de Salutinstname:Departament de Salut de la Generalitat de Catalunya (DS)InglésDisease Models & Mechanisms;14(5)https://doi.org/10.1242/dmm.048884info:eu-repo/grantAgreement/ES/PE2013-2016/PI18%2F00947info:eu-repo/grantAgreement/ES/PE2013-2016/PI17%2F00754info:eu-repo/grantAgreement/ES/PE2013-2016/AC18%2F00033Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:scientiasalut.gencat.cat:11351/67652026-06-12T09:38:37Z
score 15.811543

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