Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release

© 2022 by the authors

Detalhes bibliográficos
Autores: Jaén, Rafael I., Povo-Retana, Adrián, Rosales-Mendoza, César Eduardo, Capillas-Herrero, Patricia, Sánchez-García, Sergio, Martín-Sanz, Paloma, Mojena, Marina, Prieto, Patricia, Boscá, Lisardo
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2022
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/276259
Acesso em linha:http://hdl.handle.net/10261/276259
Access Level:Acceso aberto
Palavra-chave:PCSK9
LDL
ROS
Atherosclerosis
Macrophage
Cholesterol
TLR4
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spelling Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species ReleaseJaén, Rafael I.Povo-Retana, AdriánRosales-Mendoza, César EduardoCapillas-Herrero, PatriciaSánchez-García, SergioMartín-Sanz, PalomaMojena, MarinaPrieto, PatriciaBoscá, LisardoPCSK9LDLROSAtherosclerosisMacrophageCholesterolTLR4© 2022 by the authorsAtherosclerosis is a cardiovascular disease caused mainly by dyslipidemia and is characterized by the formation of an atheroma plaque and chronic inflammation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that induces the degradation of the LDL receptor (LDLR), which contributes to increased levels of LDL cholesterol and the progress of atherosclerosis. Given that macrophages are relevant components of the lipidic and inflammatory environment of atherosclerosis, we studied the effects of PCSK9 treatment on human macrophages. Our data show that human macrophages do not express PCSK9 but rapidly incorporate the circulating protein through the LDLR and also activate the pro-inflammatory TLR4 pathway. Both LDLR and TLR4 are internalized after incubation of macrophages with exogenous PCSK9. PCSK9 uptake increases the production of reactive oxygen species and reduces the expression of genes involved in lipid metabolism and cholesterol efflux, while enhancing the production of pro-inflammatory cytokines through a TLR4-dependent mechanism. Under these conditions, the viability of macrophages is compromised, leading to increased cell death. These results provide novel insights into the role of PCSK9 in the crosstalk of lipids and cholesterol metabolism through the LDLR and on the pro-inflammatory activation of macrophages through TLR4 signaling. These pathways are relevant in the outcome of atherosclerosis and highlight the relevance of PCSK9 as a therapeutic target for the treatment of cardiovascular diseases.This work has been supported by Consejo Superior de Investigaciones Científicas (PIE202020E260), Ministerio de Ciencia, Investigación y Universidades, Agencia Estatal de Investigación 10.13039/501100011033 (PID2019-104284RB-I00, PID2020-113238RB-I00), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222) and Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686, Fondo Social Europeo, and Fondo Europeo de Desarrollo Regional.Peer reviewedMultidisciplinary Digital Publishing InstituteConsejo Superior de Investigaciones Científicas (España)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (España)Comunidad de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/276259reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104284RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-113238RB-I00S2017/BMD-3686/CIFRA2-CMhttps://doi.org/10.3390/ijms23169114Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2762592026-05-22T06:33:51Z
dc.title.none.fl_str_mv Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release
title Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release
spellingShingle Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release
Jaén, Rafael I.
PCSK9
LDL
ROS
Atherosclerosis
Macrophage
Cholesterol
TLR4
title_short Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release
title_full Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release
title_fullStr Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release
title_full_unstemmed Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release
title_sort Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release
dc.creator.none.fl_str_mv Jaén, Rafael I.
Povo-Retana, Adrián
Rosales-Mendoza, César Eduardo
Capillas-Herrero, Patricia
Sánchez-García, Sergio
Martín-Sanz, Paloma
Mojena, Marina
Prieto, Patricia
Boscá, Lisardo
author Jaén, Rafael I.
author_facet Jaén, Rafael I.
Povo-Retana, Adrián
Rosales-Mendoza, César Eduardo
Capillas-Herrero, Patricia
Sánchez-García, Sergio
Martín-Sanz, Paloma
Mojena, Marina
Prieto, Patricia
Boscá, Lisardo
author_role author
author2 Povo-Retana, Adrián
Rosales-Mendoza, César Eduardo
Capillas-Herrero, Patricia
Sánchez-García, Sergio
Martín-Sanz, Paloma
Mojena, Marina
Prieto, Patricia
Boscá, Lisardo
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Consejo Superior de Investigaciones Científicas (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (España)
Comunidad de Madrid
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv PCSK9
LDL
ROS
Atherosclerosis
Macrophage
Cholesterol
TLR4
topic PCSK9
LDL
ROS
Atherosclerosis
Macrophage
Cholesterol
TLR4
description © 2022 by the authors
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/276259
url http://hdl.handle.net/10261/276259
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104284RB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-113238RB-I00
S2017/BMD-3686/CIFRA2-CM
https://doi.org/10.3390/ijms23169114
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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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