Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation

Objective-Atherosclerosis and restenosis are multifactorial diseases associated with abnormal vascular smooth muscle cell (VSMC) proliferation. Nuclear factor-Y (NF-Y) plays a major role in transcriptional activation of the CYCLIN B1 gene (CCNB1), a key positive regulator of cell proliferation and n...

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Authors: Silvestre-Roig, C, Fernandez, P, Esteban, V, Pello, OM, Indolfi, C, Rodriguez, C, Rodriguez-Calvo, R, Lopez-Maderuelo, MD, Bauriedel, G, Hutter, R, Fuster, V, Ibanez, B, Redondo, JM, Martinez-Gonzalez, J, Andres, V
Format: article
Status:Published version
Publication Date:2013
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p10086
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10086
Access Level:Open access
Keyword:atherosclerosis
cyclin B1
nuclear factor-Y
restenosis
vascular smooth muscle cell proliferation
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spelling Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima FormationSilvestre-Roig, CFernandez, PEsteban, VPello, OMIndolfi, CRodriguez, CRodriguez-Calvo, RLopez-Maderuelo, MDBauriedel, GHutter, RFuster, VIbanez, BRedondo, JMMartinez-Gonzalez, JAndres, Vatherosclerosiscyclin B1nuclear factor-Yrestenosisvascular smooth muscle cell proliferationObjective-Atherosclerosis and restenosis are multifactorial diseases associated with abnormal vascular smooth muscle cell (VSMC) proliferation. Nuclear factor-Y (NF-Y) plays a major role in transcriptional activation of the CYCLIN B1 gene (CCNB1), a key positive regulator of cell proliferation and neointimal thickening. Here, we investigated the role of NF-Y in occlusive vascular disease. Approach and Results-We performed molecular and expression studies in cultured cells, animal models, and human tissues. We find upregulation of NF-Y and cyclin B1 expression in proliferative regions of murine atherosclerotic plaques and mechanically induced lesions, which correlates with higher binding of NF-Y to target sequences in the CCNB1 promoter. NF-YA expression in neointimal lesions is detected in VSMCs, macrophages, and endothelial cells. Platelet-derived growth factor-BB, a main inductor of VSMC growth and neointima development, induces the recruitment of NF-Y to the CCNB1 promoter and augments both CCNB1 mRNA expression and cell proliferation through extracellular signal-regulated kinase 1/2 and Akt activation in rat and human VSMCs. Moreover, adenovirus-mediated overexpression of a NF-YA-dominant negative mutant inhibits platelet-derived growth factor-BB-induced CCNB1 expression and VSMC proliferation in vitro and neointimal lesion formation in a mouse model of femoral artery injury. We also detect NF-Y expression and DNA-binding activity in human neointimal lesions. Conclusions-Our results identify NF-Y as a key downstream effector of the platelet-derived growth factor-BB-dependent mitogenic pathway that is activated in experimental and human vasculoproliferative diseases. They also identify NF-Y inhibition as a novel and attractive strategy for the local treatment of neointimal formation induced by vessel denudation. (Arterioscler Thromb Vasc Biol. 2013; 33:1036-1045.)LIPPINCOTT WILLIAMS & WILKINS2013info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10086ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGYISSN: 10795642ISSNe: 15244636reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p100862026-06-14T12:41:47Z
dc.title.none.fl_str_mv Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
title Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
spellingShingle Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
Silvestre-Roig, C
atherosclerosis
cyclin B1
nuclear factor-Y
restenosis
vascular smooth muscle cell proliferation
title_short Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
title_full Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
title_fullStr Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
title_full_unstemmed Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
title_sort Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
dc.creator.none.fl_str_mv Silvestre-Roig, C
Fernandez, P
Esteban, V
Pello, OM
Indolfi, C
Rodriguez, C
Rodriguez-Calvo, R
Lopez-Maderuelo, MD
Bauriedel, G
Hutter, R
Fuster, V
Ibanez, B
Redondo, JM
Martinez-Gonzalez, J
Andres, V
author Silvestre-Roig, C
author_facet Silvestre-Roig, C
Fernandez, P
Esteban, V
Pello, OM
Indolfi, C
Rodriguez, C
Rodriguez-Calvo, R
Lopez-Maderuelo, MD
Bauriedel, G
Hutter, R
Fuster, V
Ibanez, B
Redondo, JM
Martinez-Gonzalez, J
Andres, V
author_role author
author2 Fernandez, P
Esteban, V
Pello, OM
Indolfi, C
Rodriguez, C
Rodriguez-Calvo, R
Lopez-Maderuelo, MD
Bauriedel, G
Hutter, R
Fuster, V
Ibanez, B
Redondo, JM
Martinez-Gonzalez, J
Andres, V
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv atherosclerosis
cyclin B1
nuclear factor-Y
restenosis
vascular smooth muscle cell proliferation
topic atherosclerosis
cyclin B1
nuclear factor-Y
restenosis
vascular smooth muscle cell proliferation
description Objective-Atherosclerosis and restenosis are multifactorial diseases associated with abnormal vascular smooth muscle cell (VSMC) proliferation. Nuclear factor-Y (NF-Y) plays a major role in transcriptional activation of the CYCLIN B1 gene (CCNB1), a key positive regulator of cell proliferation and neointimal thickening. Here, we investigated the role of NF-Y in occlusive vascular disease. Approach and Results-We performed molecular and expression studies in cultured cells, animal models, and human tissues. We find upregulation of NF-Y and cyclin B1 expression in proliferative regions of murine atherosclerotic plaques and mechanically induced lesions, which correlates with higher binding of NF-Y to target sequences in the CCNB1 promoter. NF-YA expression in neointimal lesions is detected in VSMCs, macrophages, and endothelial cells. Platelet-derived growth factor-BB, a main inductor of VSMC growth and neointima development, induces the recruitment of NF-Y to the CCNB1 promoter and augments both CCNB1 mRNA expression and cell proliferation through extracellular signal-regulated kinase 1/2 and Akt activation in rat and human VSMCs. Moreover, adenovirus-mediated overexpression of a NF-YA-dominant negative mutant inhibits platelet-derived growth factor-BB-induced CCNB1 expression and VSMC proliferation in vitro and neointimal lesion formation in a mouse model of femoral artery injury. We also detect NF-Y expression and DNA-binding activity in human neointimal lesions. Conclusions-Our results identify NF-Y as a key downstream effector of the platelet-derived growth factor-BB-dependent mitogenic pathway that is activated in experimental and human vasculoproliferative diseases. They also identify NF-Y inhibition as a novel and attractive strategy for the local treatment of neointimal formation induced by vessel denudation. (Arterioscler Thromb Vasc Biol. 2013; 33:1036-1045.)
publishDate 2013
dc.date.none.fl_str_mv 2013
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://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10086
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10086
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 LIPPINCOTT WILLIAMS & WILKINS
publisher.none.fl_str_mv LIPPINCOTT WILLIAMS & WILKINS
dc.source.none.fl_str_mv ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
ISSN: 10795642
ISSNe: 15244636
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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