Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells

Objective-Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, in...

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Autores: Glineur, Corine, Gross, Barbara, Neve, Bernadette, Rommens, Corinne, Chew, Gerard T., Marin-Nizard, Françoise, Rodríguez-Pascual, Fernando, Lamas Peláez, Santiago, Watts, Gerard F., Staels, Bart
Tipo de recurso: artículo
Fecha de publicación:2013
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/95891
Acceso en línea:http://hdl.handle.net/10261/95891
Access Level:acceso abierto
Palabra clave:Endothelium
Glycogen synthase kinase-3
Peroxisome proliferator–activated receptor-α
Type 2 diabetes mellitus
Endothelin-1
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spelling Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cellsGlineur, CorineGross, BarbaraNeve, BernadetteRommens, CorinneChew, Gerard T.Marin-Nizard, FrançoiseRodríguez-Pascual, FernandoLamas Peláez, SantiagoWatts, Gerard F.Staels, BartEndotheliumGlycogen synthase kinase-3Peroxisome proliferator–activated receptor-αType 2 diabetes mellitusEndothelin-1Objective-Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients. Methods and Results-FF impaired the capacity of transforming growth factor-β to induce ET-1 gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-β-stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3β phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of ET-1 gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1. Conclusion-FF decreases ET-1 expression by a PPARα-dependent mechanism, via transcriptional induction of the Krüppel-like factor 11 repressor and by PPARα-independent actions via inhibition of glycogen synthase kinase-3 activity. © 2013 American Heart Association, Inc.Région Nord-Pas de Calais/FEDER; Fondation Coeur et Artères; National Health and Medical Research Council (NHMRC) of Australia; NHMRC medical scholarship; French National Research Agency (ANR) Institut National de la Santé et de la Recherche Médicale; Centre National de la Recherche Scientifique; Institut Universitaire de FrancePeer ReviewedAmerican Heart Association2014201420132014info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/95891reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglésinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/958912026-05-22T06:33:51Z
dc.title.none.fl_str_mv Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells
title Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells
spellingShingle Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells
Glineur, Corine
Endothelium
Glycogen synthase kinase-3
Peroxisome proliferator–activated receptor-α
Type 2 diabetes mellitus
Endothelin-1
title_short Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells
title_full Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells
title_fullStr Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells
title_full_unstemmed Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells
title_sort Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells
dc.creator.none.fl_str_mv Glineur, Corine
Gross, Barbara
Neve, Bernadette
Rommens, Corinne
Chew, Gerard T.
Marin-Nizard, Françoise
Rodríguez-Pascual, Fernando
Lamas Peláez, Santiago
Watts, Gerard F.
Staels, Bart
author Glineur, Corine
author_facet Glineur, Corine
Gross, Barbara
Neve, Bernadette
Rommens, Corinne
Chew, Gerard T.
Marin-Nizard, Françoise
Rodríguez-Pascual, Fernando
Lamas Peláez, Santiago
Watts, Gerard F.
Staels, Bart
author_role author
author2 Gross, Barbara
Neve, Bernadette
Rommens, Corinne
Chew, Gerard T.
Marin-Nizard, Françoise
Rodríguez-Pascual, Fernando
Lamas Peláez, Santiago
Watts, Gerard F.
Staels, Bart
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Endothelium
Glycogen synthase kinase-3
Peroxisome proliferator–activated receptor-α
Type 2 diabetes mellitus
Endothelin-1
topic Endothelium
Glycogen synthase kinase-3
Peroxisome proliferator–activated receptor-α
Type 2 diabetes mellitus
Endothelin-1
description Objective-Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients. Methods and Results-FF impaired the capacity of transforming growth factor-β to induce ET-1 gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-β-stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3β phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of ET-1 gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1. Conclusion-FF decreases ET-1 expression by a PPARα-dependent mechanism, via transcriptional induction of the Krüppel-like factor 11 repressor and by PPARα-independent actions via inhibition of glycogen synthase kinase-3 activity. © 2013 American Heart Association, Inc.
publishDate 2013
dc.date.none.fl_str_mv 2013
2014
2014
2014
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/95891
url http://hdl.handle.net/10261/95891
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Heart Association
publisher.none.fl_str_mv American Heart Association
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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