Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction

Objective TNFα is a pro-inflammatory cytokine that induces endothelial dysfunction and promotes atherosclerosis progression. Down-regulation of lysyl oxidase (LOX), a key enzyme in extracellular matrix maturation, by pro-atherogenic risk factors such as LDL and homocysteine, is associated with an im...

Descripción completa

Detalles Bibliográficos
Autores: Rodríguez-Sinovas, Cristina, Alcudia, Javier F., Martínez-González, José, Raposo, Berta, Navarro, María A., Badimón Maestro, Lina
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2008
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/413465
Acceso en línea:http://hdl.handle.net/10261/413465
https://api.elsevier.com/content/abstract/scopus_id/38349121602
Access Level:acceso abierto
Palabra clave:Atherosclerosis
Endothelial dysfunction
Lysyl oxidase
TNFα
id ES_20199c29b60b4e2a851a2d8c6977efd4
oai_identifier_str oai:digital.csic.es:10261/413465
network_acronym_str ES
network_name_str España
repository_id_str
spelling Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunctionRodríguez-Sinovas, CristinaAlcudia, Javier F.Martínez-González, JoséRaposo, BertaNavarro, María A.Badimón Maestro, LinaAtherosclerosisEndothelial dysfunctionLysyl oxidaseTNFαObjective TNFα is a pro-inflammatory cytokine that induces endothelial dysfunction and promotes atherosclerosis progression. Down-regulation of lysyl oxidase (LOX), a key enzyme in extracellular matrix maturation, by pro-atherogenic risk factors such as LDL and homocysteine, is associated with an impairment of endothelial barrier function. Our hypothesis is that the inflammatory cytokine TNFα could also modulate LOX expression/function in endothelial cells. Methods The study was carried out in human umbilical vein endothelial cells (HUVEC), porcine aortic endothelial cells (PAEC) and bovine aortic endothelial cells (BAEC). LOX mRNA levels were analysed by real-time PCR and LOX activity was assessed by a high sensitive fluorescent assay. Promoter activity was determined by transient transfection using a luciferase reporter system. Results TNFα decreases LOX mRNA levels in endothelial cells in a dose- and time-dependent manner. The effect of TNFα was observed at low concentrations (0.1–1 ng/mL) and was maximal at 2.5 ng/mL (after 21 h). In transfection assays, TNFα reduced LOX transcriptional activity to a similar extent than LOX mRNA. Furthermore, TNFα decreases endothelial LOX enzymatic activity. By using both TNF receptor (TNFR) agonist and blocking antibodies we determined the involvement of TNFR2 on LOX down-regulation. Moreover, while TNFR-associated factor-2 (TRAF-2) did not mediate signalling events leading to LOX inhibition, PKC inhibitors counteracted the TNFα-induced decrease of LOX mRNA levels. Finally, TNFα administration significantly reduced vascular LOX expression in rat aorta. Conclusions Endothelial dysfunction induced by TNFα is associated with a decrease of LOX expression/activity. Thus, LOX seems to be involved in the impairment of endothelial function triggered by different pathological conditions.This study has been possible, thanks to funds provided by Fondo de Investigaciones Sanitarias PI061480, SAF 2006-07378, SAF 2006-10091, Recava (RD06/0014/0027) and CB0603. We thank Dr. Kirschman and Dr. Brink for providing the antibody against LOX and the TRAF-2 dominant-negative, respectively. Authors are indebt to Silvia Aguiló for her technical assistance.Peer reviewedElsevier BVMinisterio de Sanidad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262008info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttp://hdl.handle.net/10261/413465https://api.elsevier.com/content/abstract/scopus_id/38349121602reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1016/j.atherosclerosis.2007.06.002Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4134652026-05-22T06:33:51Z
dc.title.none.fl_str_mv Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction
title Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction
spellingShingle Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction
Rodríguez-Sinovas, Cristina
Atherosclerosis
Endothelial dysfunction
Lysyl oxidase
TNFα
title_short Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction
title_full Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction
title_fullStr Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction
title_full_unstemmed Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction
title_sort Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction
dc.creator.none.fl_str_mv Rodríguez-Sinovas, Cristina
Alcudia, Javier F.
Martínez-González, José
Raposo, Berta
Navarro, María A.
Badimón Maestro, Lina
author Rodríguez-Sinovas, Cristina
author_facet Rodríguez-Sinovas, Cristina
Alcudia, Javier F.
Martínez-González, José
Raposo, Berta
Navarro, María A.
Badimón Maestro, Lina
author_role author
author2 Alcudia, Javier F.
Martínez-González, José
Raposo, Berta
Navarro, María A.
Badimón Maestro, Lina
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Sanidad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Atherosclerosis
Endothelial dysfunction
Lysyl oxidase
TNFα
topic Atherosclerosis
Endothelial dysfunction
Lysyl oxidase
TNFα
description Objective TNFα is a pro-inflammatory cytokine that induces endothelial dysfunction and promotes atherosclerosis progression. Down-regulation of lysyl oxidase (LOX), a key enzyme in extracellular matrix maturation, by pro-atherogenic risk factors such as LDL and homocysteine, is associated with an impairment of endothelial barrier function. Our hypothesis is that the inflammatory cytokine TNFα could also modulate LOX expression/function in endothelial cells. Methods The study was carried out in human umbilical vein endothelial cells (HUVEC), porcine aortic endothelial cells (PAEC) and bovine aortic endothelial cells (BAEC). LOX mRNA levels were analysed by real-time PCR and LOX activity was assessed by a high sensitive fluorescent assay. Promoter activity was determined by transient transfection using a luciferase reporter system. Results TNFα decreases LOX mRNA levels in endothelial cells in a dose- and time-dependent manner. The effect of TNFα was observed at low concentrations (0.1–1 ng/mL) and was maximal at 2.5 ng/mL (after 21 h). In transfection assays, TNFα reduced LOX transcriptional activity to a similar extent than LOX mRNA. Furthermore, TNFα decreases endothelial LOX enzymatic activity. By using both TNF receptor (TNFR) agonist and blocking antibodies we determined the involvement of TNFR2 on LOX down-regulation. Moreover, while TNFR-associated factor-2 (TRAF-2) did not mediate signalling events leading to LOX inhibition, PKC inhibitors counteracted the TNFα-induced decrease of LOX mRNA levels. Finally, TNFα administration significantly reduced vascular LOX expression in rat aorta. Conclusions Endothelial dysfunction induced by TNFα is associated with a decrease of LOX expression/activity. Thus, LOX seems to be involved in the impairment of endothelial function triggered by different pathological conditions.
publishDate 2008
dc.date.none.fl_str_mv 2008
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/413465
https://api.elsevier.com/content/abstract/scopus_id/38349121602
url http://hdl.handle.net/10261/413465
https://api.elsevier.com/content/abstract/scopus_id/38349121602
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1016/j.atherosclerosis.2007.06.002
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
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
_version_ 1869404439352180736
score 15,812429

Similares en LA Referencia