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...
| Authors: | ; ; ; ; ; ; ; |
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| 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 |
| _version_ | 1878739539109871616 |
|---|---|
| author | García-Arguinzonis, Maisa|||0000-0001-6749-5026 |
| 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 |
| author_browse | Badimon, Lina|||0000-0002-9162-2459 Diaz-Riera, Elisa|||0000-0002-6211-4877 Escate, Rafael|||0000-0002-8448-7244 García-Arguinzonis, Maisa|||0000-0001-6749-5026 Juan-Babot, Oriol|||0000-0002-4328-0335 Mata, Pedro Padró, Teresa|||0000-0003-1921-954X Peña, Esther|||0000-0003-2750-0614 |
| 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 |
| collection | Dipòsit Digital de Documents de la UAB |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_c3659cd162d95b50ce7b25a46bf92aed |
| institution | Universitat Autònoma de Barcelona |
| instname_str | Universitat Autònoma de Barcelona |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:ddd.uab.cat:269717 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| reponame_str | Dipòsit Digital de Documents de la UAB |
| spelling | Alternative c3 complement system Lipids and atherosclerosis 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 Atherosclerosis Cardiovascular disease Complement system Proteomics Mass spectrometry 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. https://ddd.uab.cat/record/269717 https://dx.doi.org/urn:doi:10.3390/ijms22105122 |
| spellingShingle | Alternative c3 complement system García-Arguinzonis, Maisa|||0000-0001-6749-5026 Atherosclerosis Cardiovascular disease Complement system Proteomics Mass spectrometry |
| title | Alternative c3 complement system |
| title_full | Alternative c3 complement system |
| title_fullStr | Alternative c3 complement system |
| title_full_unstemmed | Alternative c3 complement system |
| title_short | Alternative c3 complement system |
| title_sort | Alternative c3 complement system |
| topic | Atherosclerosis Cardiovascular disease Complement system Proteomics Mass spectrometry |
| topic_facet | Atherosclerosis Cardiovascular disease Complement system Proteomics Mass spectrometry |
| url | https://ddd.uab.cat/record/269717 https://dx.doi.org/urn:doi:10.3390/ijms22105122 |