Alternative C3 Complement System: Lipids and Atherosclerosis
| Autor: | Garcia-Arguinzonis, M., Diaz-Riera, Elisa, Peña, Esther, Escate, Rafael, Juan-Babot, Oriol, Mata, P., Badimon, Lina, Padró, Teresa, Universitat Autònoma de Barcelona |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Vascular smooth muscle Proteome 030204 cardiovascular system & hematology Muscle Smooth Vascular Extracellular matrix 0302 clinical medicine cardiovascular disease Biology (General) Receptor Spectroscopy Cells Cultured mass spectrometry biology Chemistry General Medicine Complement C3 Middle Aged Computer Science Applications Cell biology lipids (amino acids peptides and proteins) Female medicine.symptom Adult QH301-705.5 Integrin Myocytes Smooth Muscle Inflammation Vascular Remodeling Catalysis Article Inorganic Chemistry Hyperlipoproteinemia Type II 03 medical and health sciences Young Adult proteomics medicine Cell Adhesion Humans Anaphylatoxin Physical and Theoretical Chemistry QD1-999 Molecular Biology complement system Wound Healing Organic Chemistry Atherosclerosis Complement system 030104 developmental biology Case-Control Studies biology.protein iC3b atherosclerosis |
| Zdroj: | INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau instname International Journal of Molecular Sciences Volume 22 Issue 10 International Journal of Molecular Sciences, Vol 22, Iss 5122, p 5122 (2021) |
| ISSN: | 1422-0067 |
| Popis: | 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 αMβ2 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. |
| Databáze: | OpenAIRE |
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