Alternative C3 Complement System: Lipids and Atherosclerosis
Por:
Garcia-Arguinzonis, M, Diaz-Riera, E, Pena, E, Escate, R, Juan-Babot, O, Mata, P, Badimon, L, Padro, T
Publicada:
1 may 2021
Resumen:
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 alpha(M)beta(2) 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.
Filiaciones:
Garcia-Arguinzonis, M:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Barcelona 08025, Spain
Diaz-Riera, E:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Barcelona 08025, Spain
Pena, E:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Barcelona 08025, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Cardiovasc CIBERCV, Madrid 28029, Spain
Escate, R:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Barcelona 08025, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Cardiovasc CIBERCV, Madrid 28029, Spain
Juan-Babot, O:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Barcelona 08025, Spain
Mata, P:
Fdn Hipercolesterolemia Familiar, Madrid 28010, Spain
Badimon, L:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Barcelona 08025, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Cardiovasc CIBERCV, Madrid 28029, Spain
UAB, Cardiovasc Res Chair, Barcelona 08025, Spain
Padro, T:
Hosp Santa Creu & Sant Pau, Res Inst, Cardiovasc Program ICCC, IIB St Pau, Barcelona 08025, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Cardiovasc CIBERCV, Madrid 28029, Spain
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