Alternative c3 complement system : Lipids and atherosclerosis
García-Arguinzonis, Maisa (Cardiovascular Program-ICCC)
Diaz-Riera, Elisa (Institut d'Investigació Biomèdica Sant Pau)
Peña, Esther (Institut d'Investigació Biomèdica Sant Pau)
Escate, Rafael (Institut d'Investigació Biomèdica Sant Pau)
Juan-Babot, Oriol (Institut d'Investigació Biomèdica Sant Pau)
Mata, Pedro (Fundación Hipercolesterolemia Familiar)
Badimon, Lina (Institut d'Investigació Biomèdica Sant Pau)
Padró, Teresa (Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	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.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1480 Agencia Estatal de Investigación PID2019-107160RB-I00 Instituto de Salud Carlos III PI19/01687 Ministerio de Economía y Competitividad RD16/0011/0018
Nota:	Altres ajuts: Fundación Jesus Serra
Nota:	Altres ajuts: Fundación de Investigación Cardiovascular
Nota:	Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER)
Drets:	Aquest 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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Atherosclerosis ; Cardiovascular disease ; Complement system ; Proteomics ; Mass spectrometry
Publicat a:	International journal of molecular sciences, Vol. 22 Núm. 10 (february 2021) , p. 5122, ISSN 1422-0067

DOI: 10.3390/ijms22105122
PMID: 34066088

17 p, 2.1 MB

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