Alternative c3 complement system

Familial hypercholesterolemia (FH) is increasingly associated with inflammation, a phenotype that persists despite treatment with lipid lowering therapies. The alternative C3 complement system (C3), as a key inflammatory mediator, seems to be involved in the atherosclerotic process; however, the rel...

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Authors: García-Arguinzonis, Maisa|||0000-0001-6749-5026, Diaz-Riera, Elisa|||0000-0002-6211-4877, Peña, Esther|||0000-0003-2750-0614, Escate, Rafael|||0000-0002-8448-7244, Juan-Babot, Oriol|||0000-0002-4328-0335, Mata, Pedro, Badimon, Lina|||0000-0002-9162-2459, Padró, Teresa|||0000-0003-1921-954X
Format: article
Publication Date:2021
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:269717
Online Access:https://ddd.uab.cat/record/269717
https://dx.doi.org/urn:doi:10.3390/ijms22105122
Access Level:Open access
Keyword:Atherosclerosis
Cardiovascular disease
Complement system
Proteomics
Mass spectrometry
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spelling Alternative c3 complement systemLipids and atherosclerosisGarcía-Arguinzonis, Maisa|||0000-0001-6749-5026Diaz-Riera, Elisa|||0000-0002-6211-4877Peña, Esther|||0000-0003-2750-0614Escate, Rafael|||0000-0002-8448-7244Juan-Babot, Oriol|||0000-0002-4328-0335Mata, PedroBadimon, Lina|||0000-0002-9162-2459Padró, Teresa|||0000-0003-1921-954XAtherosclerosisCardiovascular diseaseComplement systemProteomicsMass spectrometryFamilial hypercholesterolemia (FH) is increasingly associated with inflammation, a phenotype that persists despite treatment with lipid lowering therapies. The alternative C3 complement system (C3), as a key inflammatory mediator, seems to be involved in the atherosclerotic process; however, the relationship between C3 and lipids during plaque progression remains unknown. The aim of the study was to investigate by a systems biology approach the role of C3 in relation to lipoprotein levels during atherosclerosis (AT) progression and to gain a better understanding on the effects of C3 products on the phenotype and function of human lipid-loaded vascular smooth muscle cells (VSMCs). By mass spectrometry and differential proteomics, we found the extracellular matrix (ECM) of human aortas to be enriched in active components of the C3 complement system, with a significantly different proteomic signature in AT segments. Thus, C3 products were more abundant in AT-ECM than in macroscopically normal segments. Furthermore, circulating C3 levels were significantly elevated in FH patients with subclinical coronary AT, evidenced by computed tomographic angiography. However, no correlation was identified between circulating C3 levels and the increase in plaque burden, indicating a local regulation of the C3 in AT arteries. In cell culture studies of human VSMCs, we evidenced the expression of C3, C3aR (anaphylatoxin receptor) and the integrin α β receptor for C3b/iC3b (RT-PCR and Western blot). C3mRNA was up-regulated in lipid-loaded human VSMCs, and C3 protein significantly increased in cell culture supernatants, indicating that the C3 products in the AT-ECM have a local vessel-wall niche. Interestingly, C3a and iC3b (C3 active fragments) have functional effects on VSMCs, significantly reversing the inhibition of VSMC migration induced by aggregated LDL and stimulating cell spreading, organization of F-actin stress fibers and attachment during the adhesion of lipid-loaded human VSMCs. This study, by using a systems biology approach, identified molecular processes involving the C3 complement system in vascular remodeling and in the progression of advanced human atherosclerotic lesions.Universitat Autònoma de Barcelona 22021-01-0120212021-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/269717https://dx.doi.org/urn:doi:10.3390/ijms22105122reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-1480Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-107160RB-I00Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI19/01687Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 RD16/0011/0018open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2697172026-06-06T12:50:31Z
dc.title.none.fl_str_mv Alternative c3 complement system
Lipids and atherosclerosis
title Alternative c3 complement system
spellingShingle Alternative c3 complement system
García-Arguinzonis, Maisa|||0000-0001-6749-5026
Atherosclerosis
Cardiovascular disease
Complement system
Proteomics
Mass spectrometry
title_short Alternative c3 complement system
title_full Alternative c3 complement system
title_fullStr Alternative c3 complement system
title_full_unstemmed Alternative c3 complement system
title_sort Alternative c3 complement system
dc.creator.none.fl_str_mv García-Arguinzonis, Maisa|||0000-0001-6749-5026
Diaz-Riera, Elisa|||0000-0002-6211-4877
Peña, Esther|||0000-0003-2750-0614
Escate, Rafael|||0000-0002-8448-7244
Juan-Babot, Oriol|||0000-0002-4328-0335
Mata, Pedro
Badimon, Lina|||0000-0002-9162-2459
Padró, Teresa|||0000-0003-1921-954X
author García-Arguinzonis, Maisa|||0000-0001-6749-5026
author_facet García-Arguinzonis, Maisa|||0000-0001-6749-5026
Diaz-Riera, Elisa|||0000-0002-6211-4877
Peña, Esther|||0000-0003-2750-0614
Escate, Rafael|||0000-0002-8448-7244
Juan-Babot, Oriol|||0000-0002-4328-0335
Mata, Pedro
Badimon, Lina|||0000-0002-9162-2459
Padró, Teresa|||0000-0003-1921-954X
author_role author
author2 Diaz-Riera, Elisa|||0000-0002-6211-4877
Peña, Esther|||0000-0003-2750-0614
Escate, Rafael|||0000-0002-8448-7244
Juan-Babot, Oriol|||0000-0002-4328-0335
Mata, Pedro
Badimon, Lina|||0000-0002-9162-2459
Padró, Teresa|||0000-0003-1921-954X
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv Atherosclerosis
Cardiovascular disease
Complement system
Proteomics
Mass spectrometry
topic Atherosclerosis
Cardiovascular disease
Complement system
Proteomics
Mass spectrometry
description Familial hypercholesterolemia (FH) is increasingly associated with inflammation, a phenotype that persists despite treatment with lipid lowering therapies. The alternative C3 complement system (C3), as a key inflammatory mediator, seems to be involved in the atherosclerotic process; however, the relationship between C3 and lipids during plaque progression remains unknown. The aim of the study was to investigate by a systems biology approach the role of C3 in relation to lipoprotein levels during atherosclerosis (AT) progression and to gain a better understanding on the effects of C3 products on the phenotype and function of human lipid-loaded vascular smooth muscle cells (VSMCs). By mass spectrometry and differential proteomics, we found the extracellular matrix (ECM) of human aortas to be enriched in active components of the C3 complement system, with a significantly different proteomic signature in AT segments. Thus, C3 products were more abundant in AT-ECM than in macroscopically normal segments. Furthermore, circulating C3 levels were significantly elevated in FH patients with subclinical coronary AT, evidenced by computed tomographic angiography. However, no correlation was identified between circulating C3 levels and the increase in plaque burden, indicating a local regulation of the C3 in AT arteries. In cell culture studies of human VSMCs, we evidenced the expression of C3, C3aR (anaphylatoxin receptor) and the integrin α β receptor for C3b/iC3b (RT-PCR and Western blot). C3mRNA was up-regulated in lipid-loaded human VSMCs, and C3 protein significantly increased in cell culture supernatants, indicating that the C3 products in the AT-ECM have a local vessel-wall niche. Interestingly, C3a and iC3b (C3 active fragments) have functional effects on VSMCs, significantly reversing the inhibition of VSMC migration induced by aggregated LDL and stimulating cell spreading, organization of F-actin stress fibers and attachment during the adhesion of lipid-loaded human VSMCs. This study, by using a systems biology approach, identified molecular processes involving the C3 complement system in vascular remodeling and in the progression of advanced human atherosclerotic lesions.
publishDate 2021
dc.date.none.fl_str_mv 2
2021-01-01
2021
2021-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
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 https://ddd.uab.cat/record/269717
https://dx.doi.org/urn:doi:10.3390/ijms22105122
url https://ddd.uab.cat/record/269717
https://dx.doi.org/urn:doi:10.3390/ijms22105122
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-1480
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-107160RB-I00
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI19/01687
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 RD16/0011/0018
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
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
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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