Role of complement system in pathological remodeling of the vascular wall

Martı́n-Ventura, José Luis; Martínez-López, Diego; Roldán-Montero, Raquel; Gómez-Guerrero, Carmen; Blanco-Colio, Luis Miguel

doi:10.1016/j.molimm.2019.06.016

Cited by 36 publications

(36 citation statements)

References 98 publications

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“…The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China. 2 The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. 3 Beijing Information Science & Technology University, Beijing 100192, China.…”

Section: Acknowledgementsmentioning

confidence: 99%

“…Atherosclerosis, a complex cardiovascular disease, has been reported as a chronic inflammatory disease by the increasing studies [1,2]. At different stages of atherosclerosis, the infiltration of various inflammatory cells, such as T cells, mast cells and macrophages, into the atherosclerotic plaques is one of the main characteristics of atherosclerosis [3].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit

Yang

Jia

et al. 2020

BMC Cardiovasc Disord

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Background: Previous studies have indicated that the JAK/STAT signaling pathway is involved in modulating arterial adventitia inflammation response. In this study, we designed experiments to further investigate the effect of JAK2/STAT3/SOCS3 signaling in rabbit atherosclerosis process.Methods: Atherosclerosis was induced in the abdominal arteries of rabbits by balloon injury of the aorta supplemented by the atherogenic diet. Simultaneously, in the process of atherosclerosis, animals underwent either ruxolitinib treatment or not for 12 weeks. At the end of the experimental period, all rabbits were sacrificed. The plaque areas in abdominal artery, the lipid burden of plaque and the calcium burden of plaque were detected by H&E staining, Oil Red O staining and Alizarin Red staining, respectively. In addition, rabbit plasma lipids and inflammatory cytokines were measured by biochemical test kits or ELISA kits. Finally, the expression and phosphorylation levels of JAK2/STAT3/SOCS3 pathway-related proteins were detected by RT-qPCR, western blot and immunohistochemistry assays.Results: H&E staining and CT scan analysis showed that rabbit atherosclerosis model was constructed successfully. Ruxolitinib, an inhibitor of the Janus kinase 2 (JAK2), substantially reduced the area of atherosclerotic plaques in rabbits treated with high fat diet and balloon injury of the aorta. Moreover, ruxolitinib significantly decreased IL-6, IL-1β, IFN-γ and TNF-α, but increased IL-10 and IL-17 levels in plasma of atherosclerotic rabbits. Additionally, ruxolitinib reduced plasma TC, TG and LDL-C contents and AIP value, while enhanced HDL-C level in atherosclerotic rabbits. Furthermore, we found that JAK2 and STAT3 phosphorylation were up-regulated in rabbits with atherosclerosis when compared with those of the control group, followed by the expression of SOCS3 was also increased due to the activation of JAK2 and STAT3. Interestingly, ruxolitinib could inactivate JAK2 and STAT3 pathway and decrease SOCS3 expression.Conclusion: Taken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.

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Section: Acknowledgementsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit

Yang

Jia

et al. 2020

BMC Cardiovasc Disord

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“…Accumulating evidence indicates that high levels of C3 account for an increased risk of cardiovascular disease in humans [ 19 , 22 , 32 ] especially in patients with metabolic pathologies [ 33 ]. To date, however, most of the studies addressed to investigate the involvement of the complement system in the atherosclerotic process have focused on the C5b-derived terminal pathway of the complement system (reviewed in [ 14 , 15 ]).…”

Section: Discussionmentioning

confidence: 99%

“…Atherosclerosis is widely recognized as a lipid-induced chronic inflammatory disease of the arterial wall with the activation of resident cells and recruitment of circulating leukocytes [ 13 ]. The complement system has been repeatedly associated with vascular remodeling [ 14 ] and atherosclerosis [ 15 ]. Results from experimental animal models and human samples suggest that complement activation may exert dual atheroprotective and proatherogenic effects mainly associated with the initial and terminal stages of the complement cascade, respectively [ 16 , 17 ].…”

Section: Introductionmentioning

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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“…Also, complement proteins are critical in AS. The mechanism involved is the increased expression of complement receptors and complement activators (C 1q , C 3 ) by damaged cells present in the ischemic lesion (49)(50)(51)(52)(53). These components can act both directly and indirectly.…”

Section: Molecular Mechanism Of Atherosclerosismentioning

confidence: 99%

Cross-Talk of Atherosclerosis and Ischemic Stroke: Dramatic Role of Neutrophils

2021

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Context: Current investigations illustrate the increasing prevalence of atherosclerosis (AS) through the aggravating role of inappropriate lifestyle patterns. Atherosclerosis is the cause of important vascular-related diseases such as ischemic stroke (IS). Understanding AS pathophysiology can help reduce the incidence of AS-mediated diseases like ischemic stroke. Evidence Acquisition: For this narrative review article, we used the five mega databases of PubMed, Google Scholar, Scopus, Springer, and Science Direct. We searched from 2010 Jan to 2020 Dec and based on keywords and inclusion criteria, 77 articles were enrolled. Results: Based on prior articles on atherosclerosis and ischemic stroke pathophysiology, local and systemic inflammation is a vigorous factor in both diseasesIndeed, the fundamental inflammatory pathway involved atherosclerosis, and ischemic stroke is associated with the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor-kappa B (TLR4/ Myd88/ NF-κB) cascade. The functional paw of these intricate mechanisms are pro-inflammatory mediators, such as interleukin-1 beta (IL-1β), tumor necrosis factor (TNF-α), and interleukin-18 (IL-18) incite inflammation. Besides, the essential structures termed inflammasomes (multi proteins components), and multiplicity of immune and non-immune cells (i.e., neutrophils, monocytes, platelets, and macrophages) are beneficial in the induction of inflammatory microenvironment. Conclusions: Neutrophils could be the most effective cells in the inflammation-based mechanism in IS and AS. It is clarified that neutrophils with the recruitment of own vesicles and granules can afford to amplify inflammatory conditions and be a key cell in AS and IS cross-talk. Therefore, utilizing methods to control neutrophils-mediated mechanisms could be an effective method for the prevention of AS and IS.

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Role of complement system in pathological remodeling of the vascular wall

Cited by 36 publications

References 98 publications

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit

Alternative C3 Complement System: Lipids and Atherosclerosis

Cross-Talk of Atherosclerosis and Ischemic Stroke: Dramatic Role of Neutrophils

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