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

Nerea Méndez-Barbero, Carmen Gutierrez-Muñoz, Julio Madrigal-Matute, Pablo Mínguez, Jesús Egido, Jean Baptiste Michel, Jose L. Martín-Ventura, Vanesa Esteban, Luis M. Blanco-Colio

Research output: Contribution to journalArticle

Abstract

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 of TWEAK on vascular smooth muscle cells (VSMCs) is not completely elucidated. Methods: Next generation sequencing-based methods were performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwell migration 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 functional module 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. Fund: ISCiii-FEDER, CIBERCV and CIBERDEM.

Original languageEnglish (US)
Pages (from-to)274-289
Number of pages16
JournalEBioMedicine
Volume46
DOIs
StatePublished - Aug 2019

Fingerprint

Vascular Smooth Muscle
Angioplasty
Smooth Muscle Myocytes
Muscle
Cell proliferation
Cell Proliferation
Cell Movement
Genes
Stents
Wire
Therapeutics
Hyperplasia
Phosphotransferases
Neointima
Blocking Antibodies
Fibroblast Growth Factors
Coronary Stenosis
Wounds and Injuries
Proliferating Cell Nuclear Antigen
Femoral Artery

Keywords

  • Cyclins
  • Fn14
  • Proliferation
  • Restenosis
  • TWEAK

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Méndez-Barbero, N., Gutierrez-Muñoz, C., Madrigal-Matute, J., Mínguez, P., Egido, J., Michel, J. B., ... Blanco-Colio, L. M. (2019). A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis. EBioMedicine, 46, 274-289. https://doi.org/10.1016/j.ebiom.2019.07.072

A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis. / Méndez-Barbero, Nerea; Gutierrez-Muñoz, Carmen; Madrigal-Matute, Julio; Mínguez, Pablo; Egido, Jesús; Michel, Jean Baptiste; Martín-Ventura, Jose L.; Esteban, Vanesa; Blanco-Colio, Luis M.

In: EBioMedicine, Vol. 46, 08.2019, p. 274-289.

Research output: Contribution to journalArticle

Méndez-Barbero, N, Gutierrez-Muñoz, C, Madrigal-Matute, J, Mínguez, P, Egido, J, Michel, JB, Martín-Ventura, JL, Esteban, V & Blanco-Colio, LM 2019, 'A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis', EBioMedicine, vol. 46, pp. 274-289. https://doi.org/10.1016/j.ebiom.2019.07.072
Méndez-Barbero, Nerea ; Gutierrez-Muñoz, Carmen ; Madrigal-Matute, Julio ; Mínguez, Pablo ; Egido, Jesús ; Michel, Jean Baptiste ; Martín-Ventura, Jose L. ; Esteban, Vanesa ; Blanco-Colio, Luis M. / A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis. In: EBioMedicine. 2019 ; Vol. 46. pp. 274-289.
@article{5677ff9c77bb432783a7db398314eae1,
title = "A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis",
abstract = "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 of TWEAK on vascular smooth muscle cells (VSMCs) is not completely elucidated. Methods: Next generation sequencing-based methods were performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwell migration 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 functional module 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. Fund: ISCiii-FEDER, CIBERCV and CIBERDEM.",
keywords = "Cyclins, Fn14, Proliferation, Restenosis, TWEAK",
author = "Nerea M{\'e}ndez-Barbero and Carmen Gutierrez-Mu{\~n}oz and Julio Madrigal-Matute and Pablo M{\'i}nguez and Jes{\'u}s Egido and Michel, {Jean Baptiste} and Mart{\'i}n-Ventura, {Jose L.} and Vanesa Esteban and Blanco-Colio, {Luis M.}",
year = "2019",
month = "8",
doi = "10.1016/j.ebiom.2019.07.072",
language = "English (US)",
volume = "46",
pages = "274--289",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis

AU - Méndez-Barbero, Nerea

AU - Gutierrez-Muñoz, Carmen

AU - Madrigal-Matute, Julio

AU - Mínguez, Pablo

AU - Egido, Jesús

AU - Michel, Jean Baptiste

AU - Martín-Ventura, Jose L.

AU - Esteban, Vanesa

AU - Blanco-Colio, Luis M.

PY - 2019/8

Y1 - 2019/8

N2 - 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 of TWEAK on vascular smooth muscle cells (VSMCs) is not completely elucidated. Methods: Next generation sequencing-based methods were performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwell migration 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 functional module 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. Fund: ISCiii-FEDER, CIBERCV and CIBERDEM.

AB - 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 of TWEAK on vascular smooth muscle cells (VSMCs) is not completely elucidated. Methods: Next generation sequencing-based methods were performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwell migration 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 functional module 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. Fund: ISCiii-FEDER, CIBERCV and CIBERDEM.

KW - Cyclins

KW - Fn14

KW - Proliferation

KW - Restenosis

KW - TWEAK

UR - http://www.scopus.com/inward/record.url?scp=85070729578&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070729578&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2019.07.072

DO - 10.1016/j.ebiom.2019.07.072

M3 - Article

C2 - 31395500

AN - SCOPUS:85070729578

VL - 46

SP - 274

EP - 289

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -