Complement C5 Protein as a Marker of Subclinical Atherosclerosis

Martínez-López, Diego; Roldán-Montero, Raquel; Garcia-Marques, Fernando Jose; Núñez, Estefanía; Jorge, Inmaculada; Camafeita, Emilio; Mínguez, Pablo; Córdoba, Santiago Rodrı́guez de; López-Melgar, Beatriz; Lara‐Pezzi, Enrique; Fernández‐Ortíz, Antonio; Ibáñez, Borja; Valdivielso, José M.; Fuster, Valentín; Michel, Jean‐Baptiste; Blanco-Colio, Luis Miguel; Vázquez, Jesús; Martı́n-Ventura, José Luis

doi:10.1016/j.jacc.2020.02.058

Cited by 45 publications

(40 citation statements)

References 28 publications

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“…Furthermore, it has been reported that C5a is not induced in stable plaques and only increases in unstable plaques [46], which suggests that C5a may have a key role in the pathogenesis inducing plaque rupture. In addition, similar to the results of our study, it has been reported that plaque generation from patients with AMI and atherosclerosis increased C5 levels [47][48][49].…”

Section: Discussionsupporting

confidence: 92%

Serum biomarker discovery related to pathogenesis in acute coronary syndrome by proteomic approach

et al. 2021

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Acute coronary syndrome (ACS) results from inadequate supply of blood flow from the coronary arteries to the heart or ischemia. ACS has an extremely high morbidity and mortality. The levels of biomarkers currently used for detection of ACS also increase in response to myocardial necrosis and other diseases and are not elevated immediately after symptoms appear, thus limiting their diagnostic capacity. Therefore, we aimed to discover new ACS diagnostic biomarkers with high sensitivity and specificity that are specifically related to ACS pathogenesis. Sera from 50 patients with ACS and healthy controls (discovery cohort) each were analyzed using mass spectrometry to identify differentially expressed proteins, and protein candidates were evaluated as ACS biomarkers in 120 people in each group (validation cohort). α-1-acid glycoprotein 1, complement C5, leucine-rich α-2-glycoprotein, and vitronectin were identified as biomarkers whose levels increase and gelsolin as a biomarker whose levels decrease in patients with ACS. We concluded that these biomarkers are associated with the pathogenesis of ACS and can predict the onset of ACS prior to the appearance of necrotic biomarkers.

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Section: Discussionsupporting

confidence: 92%

Serum biomarker discovery related to pathogenesis in acute coronary syndrome by proteomic approach

et al. 2021

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“…43 C5 levels are elevated in patients with generalized subclinical atherosclerosis and considered as a novel biomarker for subclinical atherosclerosis. 44 In addition to contributing directly to the emergence and progress of CAD, C5a and C5aR signaling might also influence cardiovascular risk factors, as it has already been described for obesity 45 and arterial hypertension. 46 Nevertheless, other components of the complement cascade have already been established as prognostic markers since an increased C3/C4ratio in patients with ACS was an independent risk factor to predict another ACS in the observation period.…”

Section: Discussionmentioning

confidence: 94%

C5 Variant rs10985126 is Associated with Mortality in Patients with Symptomatic Coronary Artery Disease

Henes

Groga‐Bada

Schaeffeler

et al. 2021

PGPM

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Background: Complement component 5a (C5a) is a highly potent anaphylatoxin with a variety of pro-inflammatory effects. C5a contributes to progression of atherosclerosis and inhibition of the receptor (C5aR) might offer a therapeutic strategy in this regard. Single nucleotide polymorphisms (SNPs) of the C5 gene may modify protein expression levels and therefore function of C5a and C5aR. This study aimed to examine associations between clinically relevant C5a SNPs and the prognosis of patients with symptomatic coronary artery disease (CAD). Furthermore, we sought to investigate the influence of C5 SNPs on C5aR platelet surface expression and circulating C5a levels. Methods: C5 variants (rs25681, rs17611, rs17216529, rs12237774, rs41258306, and rs10985126) were analyzed in a consecutive cohort of 833 patients suffering from symptomatic coronary artery disease (CAD). Circulating C5a levels were determined in 116 patients whereas C5aR platelet surface expression was measured in 473 CAD patients. Endpoints included all-cause mortality, myocardial infarction (MI), and ischemic stroke (IS). Homozygous carriers (HC) of the minor allele (rs10985126) showed significantly higher allcause mortality than major allele carriers. While we could not find significant associations between rs10985126 allele frequency and C5aR platelet surfazl ce expression, significantly elevated levels of circulating C5a were found in HC of the minor allele of the respective genotype. rs17216529 allele frequency correlated with the composite combined endpoint and bleeding events. However, since the number of HC of the minor allele of this genotype was low, we cannot draw a robust conclusion about the observed associations. Conclusion:In this study, we provide evidence for the prognostic relevance of rs10985126 in CAD patients. C5 rs10985126 may serve as a prognostic biomarker for risk stratification in high-risk CAD patients and consequently promote tailored therapies.

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“…An unresolved question, with apparently controversial findings to date, refers to the origin of the vascular components of the alternative complement system since the C3 complement is mainly synthesized in the liver [ 37 , 38 ]. In the present study, we evidenced elevated levels of circulating C3 in clinically asymptomatic patients with genetic diagnosis of FH and subclinical atherosclerosis (assessed by CTA) when compared with plasma levels in young healthy subjects, suggesting a maintained activation of the innate immune response in FH, although all patients were long-term treated with LLT as per the guidelines [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Alternative C3 Complement System: Lipids and Atherosclerosis

García-Arguinzonis

Diaz-Riera

Peña

et al. 2021

IJMS

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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.

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Complement C5 Protein as a Marker of Subclinical Atherosclerosis

Cited by 45 publications

References 28 publications

Serum biomarker discovery related to pathogenesis in acute coronary syndrome by proteomic approach

Serum biomarker discovery related to pathogenesis in acute coronary syndrome by proteomic approach

C5 Variant rs10985126 is Associated with Mortality in Patients with Symptomatic Coronary Artery Disease

Alternative C3 Complement System: Lipids and Atherosclerosis

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