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Alternative C3 Complement System: Lipids and Atherosclerosis.
Garcia-Arguinzonis, Maisa; Diaz-Riera, Elisa; Peña, Esther; Escate, Rafael; Juan-Babot, Oriol; Mata, Pedro; Badimon, Lina; Padro, Teresa.
Afiliação
  • Garcia-Arguinzonis M; Cardiovascular Program-ICCC, Research Institute-Hospital Santa Creu i Sant Pau, IIB-Sant Pau, 08025 Barcelona, Spain.
  • Diaz-Riera E; Cardiovascular Program-ICCC, Research Institute-Hospital Santa Creu i Sant Pau, IIB-Sant Pau, 08025 Barcelona, Spain.
  • Peña E; Cardiovascular Program-ICCC, Research Institute-Hospital Santa Creu i Sant Pau, IIB-Sant Pau, 08025 Barcelona, Spain.
  • Escate R; Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • Juan-Babot O; Cardiovascular Program-ICCC, Research Institute-Hospital Santa Creu i Sant Pau, IIB-Sant Pau, 08025 Barcelona, Spain.
  • Mata P; Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • Badimon L; Cardiovascular Program-ICCC, Research Institute-Hospital Santa Creu i Sant Pau, IIB-Sant Pau, 08025 Barcelona, Spain.
  • Padro T; Fundación Hipercolesterolemia Familiar, 28010 Madrid, Spain.
Int J Mol Sci ; 22(10)2021 May 12.
Article em En | MEDLINE | ID: mdl-34066088
ABSTRACT
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 αMß2 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Complemento C3 / Proteoma / Miócitos de Músculo Liso / Aterosclerose / Hiperlipoproteinemia Tipo II / Músculo Liso Vascular Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Int J Mol Sci Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Espanha País de publicação: CH / SUIZA / SUÍÇA / SWITZERLAND

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Complemento C3 / Proteoma / Miócitos de Músculo Liso / Aterosclerose / Hiperlipoproteinemia Tipo II / Músculo Liso Vascular Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Int J Mol Sci Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Espanha País de publicação: CH / SUIZA / SUÍÇA / SWITZERLAND