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


Journal

International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791

Informations de publication

Date de publication:
14 Aug 2022
Historique:
received: 24 06 2022
revised: 10 08 2022
accepted: 11 08 2022
entrez: 26 8 2022
pubmed: 27 8 2022
medline: 30 8 2022
Statut: epublish

Résumé

Atherosclerosis 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.

Identifiants

pubmed: 36012389
pii: ijms23169114
doi: 10.3390/ijms23169114
pmc: PMC9409451
pii:
doi:

Substances chimiques

Cholesterol, LDL 0
Reactive Oxygen Species 0
Receptors, LDL 0
Toll-Like Receptor 4 0
PCSK9 protein, human EC 3.4.21.-
Proprotein Convertase 9 EC 3.4.21.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Centro de Investigación en Red en Enfermedades Cardiovasculares
ID : CB16/11/00222
Organisme : AGENCIA ESTATAL DE INVESTIGACION
ID : 10.13039/501100011033 (PID2019-104284RB-I00, PID2020-113238RB-I00

Références

BMC Immunol. 2008 Nov 25;9:70
pubmed: 19032770
Annu Rev Cell Dev Biol. 2000;16:459-81
pubmed: 11031244
Redox Biol. 2019 Jun;24:101215
pubmed: 31121492
Sci Signal. 2016 Aug 23;9(442):ra85
pubmed: 27555662
J Lipid Res. 2009 Apr;50 Suppl:S382-7
pubmed: 18953058
Atherosclerosis. 2018 Jan;268:235-236
pubmed: 29102656
J Immunol Res. 2020 Oct 14;2020:2687692
pubmed: 33123601
Biomedicines. 2021 Jul 08;9(7):
pubmed: 34356856
J Pediatr. 2004 Apr;144(4):421-9
pubmed: 15069387
Adv Biol (Weinh). 2021 Nov;5(11):e2100882
pubmed: 34590442
EPMA J. 2017 Aug 14;8(4):391-402
pubmed: 29209441
Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5374-9
pubmed: 15805190
Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):80-4
pubmed: 8419946
J Leukoc Biol. 2009 Jun;85(6):966-77
pubmed: 19289601
Cardiovasc Res. 2018 Jul 15;114(9):1258-1270
pubmed: 29800275
Annu Rev Med. 2020 Jan 27;71:191-201
pubmed: 31986087
Basic Res Cardiol. 2017 Dec 09;113(1):5
pubmed: 29224086
J Biol Chem. 2001 May 11;276(19):15854-60
pubmed: 11278990
Eur Heart J Cardiovasc Pharmacother. 2019 Oct 1;5(4):237-245
pubmed: 31236571
Nat Rev Immunol. 2007 May;7(5):353-64
pubmed: 17457343
Mol Metab. 2017 Oct;6(10):1186-1197
pubmed: 29031719
Infect Immun. 2003 Mar;71(3):1513-9
pubmed: 12595470
Cell. 2012 Sep 28;151(1):138-52
pubmed: 23021221
J Biol Chem. 2006 Sep 22;281(38):27816-26
pubmed: 16857673
Cell Cycle. 2010 Jul 1;9(13):2479-80
pubmed: 21483234
Cell Death Dis. 2019 Feb 12;10(2):128
pubmed: 30755589
Biomed Rep. 2014 Mar;2(2):167-171
pubmed: 24649090
Front Immunol. 2020 Apr 23;11:724
pubmed: 32391019
Mol Cell. 2003 Oct;12(4):805-16
pubmed: 14580333
Cancers (Basel). 2020 Oct 20;12(10):
pubmed: 33092171
Atherosclerosis. 2017 Jul;262:113-122
pubmed: 28535426
Horm Res. 2007;68(2):72-82
pubmed: 17344645
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14604-9
pubmed: 17804797
Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19794-9
pubmed: 17167049
Front Cardiovasc Med. 2021 Mar 23;8:639727
pubmed: 33834043
Prostaglandins Leukot Essent Fatty Acids. 2018 Nov;138:64-70
pubmed: 27288302
Curr Atheroscler Rep. 2018 Mar 10;20(4):20
pubmed: 29525934
Eur J Clin Invest. 2021 Apr;51(4):e13459
pubmed: 33236356
Front Cardiovasc Med. 2022 Feb 18;9:763516
pubmed: 35252378
J Atheroscler Thromb. 2020 Sep 1;27(9):909-918
pubmed: 32713931
PLoS One. 2016 Jun 09;11(6):e0157230
pubmed: 27280970
Horm Mol Biol Clin Investig. 2018 Jul 31;35(2):
pubmed: 30059347
J Immunol. 2010 Jul 1;185(1):605-14
pubmed: 20498354
Front Cardiovasc Med. 2021 Oct 15;8:764038
pubmed: 34782856
Nat Immunol. 2008 Apr;9(4):361-8
pubmed: 18297073
Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Apr;1862(4):393-397
pubmed: 27368140
Mol Cell Biol. 2000 Mar;20(5):1692-8
pubmed: 10669746
Cardiovasc Res. 2021 Jul 27;117(9):2054-2068
pubmed: 32991689
Atherosclerosis. 2014 Nov;237(1):76-81
pubmed: 25222343
Clin Exp Immunol. 2012 Feb;167(2):195-205
pubmed: 22235995
Front Cardiovasc Med. 2021 Jan 20;7:594441
pubmed: 33553253
Front Biosci. 2008 Jan 01;13:453-61
pubmed: 17981560
Cardiovasc Res. 2020 Aug 1;116(10):1721-1732
pubmed: 31593224
Sci Rep. 2017 Feb 06;7:42025
pubmed: 28165022
J Biol Chem. 2008 Jan 25;283(4):2363-72
pubmed: 18039658
Curr Opin Lipidol. 2014 Oct;25(5):387-93
pubmed: 25110901
Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):258-64
pubmed: 18006857
Adv Exp Med Biol. 2020;1276:67-83
pubmed: 32705595
Front Immunol. 2019 Apr 09;10:705
pubmed: 31024544
J Biol Chem. 2007 Jun 22;282(25):18602-18612
pubmed: 17452316
Int J Mol Sci. 2021 Nov 23;22(23):
pubmed: 34884442
Cardiovasc Res. 2020 Apr 1;116(5):908-915
pubmed: 31746997
Int J Mol Sci. 2019 Jul 06;20(13):
pubmed: 31284572
FASEB J. 1999 Dec;13(15):2311-7
pubmed: 10593878
Cell. 2004 Oct 15;119(2):299-309
pubmed: 15479645
Am J Physiol Cell Physiol. 2002 Jul;283(1):C347-57
pubmed: 12055104
Signal Transduct Target Ther. 2017;2:
pubmed: 29158945
Int J Mol Sci. 2021 Apr 28;22(9):
pubmed: 33924893
Immunity. 2013 Jun 27;38(6):1092-104
pubmed: 23809160
Immunity. 2008 Aug 15;29(2):182-91
pubmed: 18701082
Circ Res. 2011 Jan 21;108(2):194-200
pubmed: 21148432

Auteurs

Rafael I Jaén (RI)

Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.

Adrián Povo-Retana (A)

Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.

César Rosales-Mendoza (C)

Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.

Patricia Capillas-Herrero (P)

Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.

Sergio Sánchez-García (S)

Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.

Paloma Martín-Sanz (P)

Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.

Marina Mojena (M)

Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.

Patricia Prieto (P)

Departamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.

Lisardo Boscá (L)

Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain.

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Classifications MeSH