A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis

Background: Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling.However, the functional effect ofTWEAK on vascular smoothmuscle cell...

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Detalles Bibliográficos
Autores: Méndez-Barbero, Nerea, Gutiérez-Muñoz, Carmen, Madrigal-Matute, Julio, Mínguez, Pablo, Egido de los Ríos, Jesús, Michel, Jean-Baptiste, Martín Ventura, José Luis, Esteban, Vanesa, Blanco-Colio, Luis M.
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/691319
Acceso en línea:http://hdl.handle.net/10486/691319
https://dx.doi.org/10.1016/j.ebiom.2019.07.072
Access Level:acceso abierto
Palabra clave:Restenosis
Proliferation
Cyclins
TWEAK
Fn14
Medicina
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spelling A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosisMéndez-Barbero, NereaGutiérez-Muñoz, CarmenMadrigal-Matute, JulioMínguez, PabloEgido de los Ríos, JesúsMichel, Jean-BaptisteMartín Ventura, José LuisEsteban, VanesaBlanco-Colio, Luis M.RestenosisProliferationCyclinsTWEAKFn14MedicinaBackground: Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling.However, the functional effect ofTWEAK on vascular smoothmuscle cells (VSMCs) is not completely elucidated. Methods: Next generation sequencing-based methodswere performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwellmigration assays were used to analyze VSMCs proliferation and migration. Mouse wire injury model was done to evaluate the role of TWEAK/Fn14 during neointimal hyperplasia. Findings: TWEAK up-regulated 1611 and down-regulated 1091 genes in VSMCs. Using a gene-set enrichment method,we found a functionalmodule involved in cell proliferation defined as the minimal network connecting top TWEAK up-regulated genes. In vitro experiments in wild-type or Tnfrsf12a deficient VSMCs demonstrated that TWEAK increased cell proliferation, VSMCs motility and migration. Mechanistically, TWEAK increased cyclins (cyclinD1), cyclin-dependent kinases (CDK4, CDK6) and decreased cyclin-dependent kinase inhibitors (p15lNK4B) mRNA and protein expression. Downregulation of p15INK4B induced by TWEAK was mediated by mitogen-activated protein kinase ERK and Akt activation. Tnfrsf12a or Tnfsf12 genetic depletion and pharmacological intervention with TWEAK blocking antibody reduced neointimal formation, decreasing cell proliferation, cyclin D1 and CDK4/6 expression, and increasing p15INK4B expression compared with wild type or IgG-treated mice in wire-injured femoral arteries. Finally, immunohistochemistry in human coronary arteries with stenosis or in-stent restenosis revealed high levels of Fn14, TWEAK and PCNA in VSMCs enriched areas of the neointima as compared with healthy coronary arteries. Interpretation: Our data define a major role of TWEAK/Fn14 in the control of VSMCs proliferation and migration during neointimal hyperplasia after wire injury in mice, and identify TWEAK/Fn14 as a potential target for treating in-stent restenosis.This work was supported by Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias ISCiii/FEDER PI13/00395; PI16/01419; PI17/ 01495) and Spanish Biomedical Research Centre in Cardiovascular Disease (CIBERCV) and Metabolic Diseases and Diabetes (CIBERDEM). PM was supported by ISCIII Miguel Servet Program (CP16/00116). CGM was supported by Fundación Conchita Rábago. NMB and VE were supported by the Spanish Ministry of Economy and Competitiveness (Juan de la Cierva IJCI-2016-29630 and Ramón y Ramón Cajal Program RyC-2013-12880, respectively). JMM has been supported a postdoctoral fellowship fromthe American Diabetes Association (Grant 1-15-MI-03) and a postdoctoral fellowship fromthe American Heart Association.Elsevier B.V.Departamento de MedicinaFacultad de MedicinaInstituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)20192019-08-05research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/691319https://dx.doi.org/10.1016/j.ebiom.2019.07.072reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6913192026-06-23T12:46:27Z
dc.title.none.fl_str_mv A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis
title A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis
spellingShingle A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis
Méndez-Barbero, Nerea
Restenosis
Proliferation
Cyclins
TWEAK
Fn14
Medicina
title_short A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis
title_full A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis
title_fullStr A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis
title_full_unstemmed A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis
title_sort A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis
dc.creator.none.fl_str_mv Méndez-Barbero, Nerea
Gutiérez-Muñoz, Carmen
Madrigal-Matute, Julio
Mínguez, Pablo
Egido de los Ríos, Jesús
Michel, Jean-Baptiste
Martín Ventura, José Luis
Esteban, Vanesa
Blanco-Colio, Luis M.
author Méndez-Barbero, Nerea
author_facet Méndez-Barbero, Nerea
Gutiérez-Muñoz, Carmen
Madrigal-Matute, Julio
Mínguez, Pablo
Egido de los Ríos, Jesús
Michel, Jean-Baptiste
Martín Ventura, José Luis
Esteban, Vanesa
Blanco-Colio, Luis M.
author_role author
author2 Gutiérez-Muñoz, Carmen
Madrigal-Matute, Julio
Mínguez, Pablo
Egido de los Ríos, Jesús
Michel, Jean-Baptiste
Martín Ventura, José Luis
Esteban, Vanesa
Blanco-Colio, Luis M.
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Medicina
Facultad de Medicina
Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)
dc.subject.none.fl_str_mv Restenosis
Proliferation
Cyclins
TWEAK
Fn14
Medicina
topic Restenosis
Proliferation
Cyclins
TWEAK
Fn14
Medicina
description Background: Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling.However, the functional effect ofTWEAK on vascular smoothmuscle cells (VSMCs) is not completely elucidated. Methods: Next generation sequencing-based methodswere performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwellmigration assays were used to analyze VSMCs proliferation and migration. Mouse wire injury model was done to evaluate the role of TWEAK/Fn14 during neointimal hyperplasia. Findings: TWEAK up-regulated 1611 and down-regulated 1091 genes in VSMCs. Using a gene-set enrichment method,we found a functionalmodule involved in cell proliferation defined as the minimal network connecting top TWEAK up-regulated genes. In vitro experiments in wild-type or Tnfrsf12a deficient VSMCs demonstrated that TWEAK increased cell proliferation, VSMCs motility and migration. Mechanistically, TWEAK increased cyclins (cyclinD1), cyclin-dependent kinases (CDK4, CDK6) and decreased cyclin-dependent kinase inhibitors (p15lNK4B) mRNA and protein expression. Downregulation of p15INK4B induced by TWEAK was mediated by mitogen-activated protein kinase ERK and Akt activation. Tnfrsf12a or Tnfsf12 genetic depletion and pharmacological intervention with TWEAK blocking antibody reduced neointimal formation, decreasing cell proliferation, cyclin D1 and CDK4/6 expression, and increasing p15INK4B expression compared with wild type or IgG-treated mice in wire-injured femoral arteries. Finally, immunohistochemistry in human coronary arteries with stenosis or in-stent restenosis revealed high levels of Fn14, TWEAK and PCNA in VSMCs enriched areas of the neointima as compared with healthy coronary arteries. Interpretation: Our data define a major role of TWEAK/Fn14 in the control of VSMCs proliferation and migration during neointimal hyperplasia after wire injury in mice, and identify TWEAK/Fn14 as a potential target for treating in-stent restenosis.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-08-05
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/691319
https://dx.doi.org/10.1016/j.ebiom.2019.07.072
url http://hdl.handle.net/10486/691319
https://dx.doi.org/10.1016/j.ebiom.2019.07.072
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier B.V.
publisher.none.fl_str_mv Elsevier B.V.
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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