scholarly journals Endonuclease V Regulates Atherosclerosis Through C‐C Motif Chemokine Ligand 2‐Mediated Monocyte Infiltration

2021 ◽  
Author(s):  
Xiang Yi Kong ◽  
Camilla Huse ◽  
Kuan Yang ◽  
Jonas Øgaard ◽  
Natalia Berges ◽  
...  
Keyword(s):  
Immune Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Atherosclerotic Lesion ◽  
Plaque Burden ◽  
Enzyme Activity Assay ◽  
Endonuclease V ◽  
Atherosclerotic Lesions ◽  
Chemokine Ligand ◽  
Atherosclerotic Process ◽  
Underlying Mechanisms

Background In cardiovascular diseases, atherosclerotic disorder are the most frequent and important with respect to morbidity and mortality. Inflammation mediated by immune cells is central in all parts of the atherosclerotic progress, and further understanding of the underlying mechanisms is needed. Growing evidence suggests that deamination of adenosine‐to‐inosine in RNA is crucial for a correct immune response; nevertheless, the role of adenosine‐to‐inosine RNA editing in atherogenesis has barely been studied. Several proteins have affinity for inosines in RNA, one being ENDOV (endonuclease V), which binds and cleaves RNA at inosines. Data on ENDOV in atherosclerosis are lacking. Methods and Results Quantitative polymerase chain reaction on ENDOV mRNA showed an increased level in human carotid atherosclerotic plaques compared with control veins. Inosine‐ribonuclease activity as measured by an enzyme activity assay is detected in immune cells relevant for the atherosclerotic process. Abolishing EndoV in atherogenic apolipoprotein E‐deficient ( ApoE −/− ) mice reduces the atherosclerotic plaque burden, both in size and lipid content. In addition, in a brain stroke model, mice without ENDOV suffer less damage than control mice. Finally, lack of EndoV reduces the recruitment of monocytes to atherosclerotic lesions in atherogenic ApoE −/− mice. Conclusions ENDOV is upregulated in human atherosclerotic lesions, and data from mice suggest that ENDOV promotes atherogenesis by enhancing the monocyte recruitment into the atherosclerotic lesion, potentially by increasing the effect of CCL2 activation on these cells.

Are primed polymorphonuclear leukocytes contributors to the high heparanase levels in hemodialysis patients?

2008 ◽  
Vol 294 (2) ◽  
pp. H651-H658 ◽  
Author(s):  
Meital Cohen-Mazor ◽  
Shifra Sela ◽  
Rafi Mazor ◽  
Neta Ilan ◽  
Israel Vlodavsky ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Polymorphonuclear Leukocytes ◽  
Atherosclerotic Lesion ◽  
Cardiovascular Complications ◽  
Chronic Hemodialysis ◽  
Dialysis Session ◽  
Rt Pcr ◽  
Protein Levels ◽  
Atherosclerotic Lesions ◽  
Atherosclerotic Process

Patients on chronic hemodialysis (HD) are at high risk for developing atherosclerosis and cardiovascular complications. Heparanase, an endoglycosidase that cleaves heparan sulfate (HS) side chains of proteoglycans, is involved in extracellular matrix degradation and, as such, may be involved in the atherosclerotic lesion progression. We hypothesize that heparanase is elevated in HD patients, partly due to its release from primed circulating polymorphonuclear leukocytes (PMNLs), undergoing degranulation. Priming of PMNLs was assessed by levels of CD11b and the rate of superoxide release. Heparanase mRNA expression in PMNLs was determined by RT-PCR. PMNL and plasma levels of heparanase were determined by immunoblotting, immunofluorescence, and flow cytometry analyses. The levels of soluble HS in plasma were measured by a competition ELISA. This study shows that PMNLs isolated from HD patients have higher mRNA and protein levels of heparanase compared with normal control (NC) subjects and that heparanase levels correlate positively with PMNL priming. Plasma levels of heparanase were higher in HD patients than in NC subjects and were further elevated after the dialysis session. In addition, heparanase expression inversely correlates with plasma HS levels. A pronounced expression of heparanase was found in human atherosclerotic lesions. The increased heparanase activity in the blood of HD patients results at least in part from the degranulation of primed PMNLs and may contribute to the acceleration of the atherosclerotic process. Our findings highlight primed PMNLs as a possible source for the increased heparanase in HD patients, posing heparanase as a new risk factor for cardiovascular complications and atherosclerosis.

scholarly journals The Serine Protease Plasmin Triggers Expression of the CC-Chemokine Ligand 20 in Dendritic CellsviaAkt/NF-κB-Dependent Pathways

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Xuehua Li ◽  
Tatiana Syrovets ◽  
Thomas Simmet
Keyword(s):  
Dendritic Cells ◽  
Immune Cells ◽  
Map Kinases ◽  
Consensus Sequences ◽  
Cc Chemokine ◽  
Atherosclerotic Lesions ◽  
Chemokine Ligand ◽  
Human Dendritic Cells ◽  
Stimulation Of ◽  
Cc Chemokine Ligand 20

The number of dendritic cells is increased in advanced atherosclerotic lesions. In addition, plasmin, which might stimulate dendritic cells, is generated in atherosclerotic lesions. Here, we investigated cytokine and chemokine induction by plasmin in human dendritic cells. In human atherosclerotic vessel sections, plasmin colocalized with dendritic cells and the CC-chemokine ligand 20 (CCL20, MIP-3α), which is important for homing of lymphocytes and dendritic cells to sites of inflammation. Stimulation of human dendritic cells with plasmin, but not with catalytically inactivated plasmin, induced transcriptional regulation of CCL20. By contrast, proinflammatory cytokines such as TNF-α, IL-1α, and IL-1βwere not induced. The plasmin-mediated CCL20 expression was preceded by activation of Akt and MAP kinases followed by activation of the transcription factor NF-κB as shown by phosphorylation of its inhibitor IκBα, by nuclear localization of p65, its phosphorylation, and binding to NF-κB consensus sequences. The plasmin-induced CCL20 expression was dependent on Akt- and ERK1/2-mediated phosphorylation of IκBαon Ser32/36 and of p65 on Ser276, whereas p38 MAPK appeared to be dispensable. Thus, plasmin triggers release of the chemokine CCL20 from dendritic cells, which might facilitate accumulation of CCR6+immune cells in areas of plasmin generation such as inflamed tissues including atherosclerotic lesions.

scholarly journals Chitinase 3 like 1 is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability

2021 ◽  
Author(s):  
Pavlos Tsantilas ◽  
Shen Lao ◽  
Zhiyuan Wu ◽  
Anne Eberhard ◽  
Greg Winski ◽  
...  
Keyword(s):  
At Risk ◽  
Smooth Muscle ◽  
Carotid Artery ◽  
Atherosclerotic Lesion ◽  
Adverse Outcomes ◽  
Plaque Burden ◽  
Cell Physiology ◽  
Mechanistic Studies ◽  
Plaque Vulnerability ◽  
Fibrous Cap

Abstract Aims  Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. Methods and results  Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. Conclusion  CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.

scholarly journals Alternative C3 Complement System: Lipids and Atherosclerosis

2021 ◽  
Vol 22 (10) ◽  
pp. 5122
Author(s):  
Maisa Garcia-Arguinzonis ◽  
Elisa Diaz-Riera ◽  
Esther Peña ◽  
Rafael Escate ◽  
Oriol Juan-Babot ◽  
...  
Keyword(s):  
Cell Culture ◽  
Systems Biology ◽  
Complement System ◽  
Computed Tomographic Angiography ◽  
Lipid Lowering ◽  
Plaque Burden ◽  
Active Components ◽  
Differential Proteomics ◽  
Computed Tomographic ◽  
Atherosclerotic Process

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.

scholarly journals Nitric oxide function in atherosclerosis

1997 ◽  
Vol 6 (1) ◽  
pp. 3-21 ◽  
Author(s):  
K. E. Matthys ◽  
H. Bult
Keyword(s):  
Nitric Oxide ◽  
Leukocyte Adhesion ◽  
Atherosclerotic Lesion ◽  
Vascular Wall ◽  
Early Event ◽  
No Production ◽  
Oxygen Intermediates ◽  
Atherosclerotic Lesions ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Atherosclerosis is a chronic inflammatory process in the intima of conduit arteries, which disturbs the endothelium-dependent regulation of the vascular tone by the labile liposoluble radical nitric oxide (NO) formed by the constitutive endothelial nitric oxide synthase (eNOS). This defect predisposes to coronary vasospasm and cardiac ischaemia, with anginal pain as the typical clinical manifestation. It is now appreciated that endothelial dysfunction is an early event in atherogenesis and that it may also involve the microcirculation, in which atherosclerotic lesions do not develop. On the other hand, the inflammatory environment in atherosclerotic plaques may result in the expression of the inducible NO synthase (iNOS) isozyme. Whether the dysfunction in endothelial NO production is causal to, or the result of, atherosclerotic lesion formation is still highly debated. Most evidence supports the hypothesis that constitutive endothelial NO release protects against atherogenesis e.g. by preventing smooth muscle cell proliferation and leukocyte adhesion. Nitric oxide generated by the inducible isozyme may be beneficial by replacing the failing endothelial production but excessive release may damage the vascular wall cells, especially in combination with reactive oxygen intermediates.

scholarly journals Statin-induced microRNAome alterations modulating inflammation pathways of peripheral blood mononuclear cells in patients with hypercholesterolemia

2020 ◽  
Vol 40 (9) ◽  
Author(s):  
Hung-Ju Lin ◽  
Sung-Liang Yu ◽  
Ta-Chen Su ◽  
Hsiu-Ching Hsu ◽  
Ming-Fong Chen ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Density Lipoprotein ◽  
Cardiovascular Risks ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Abstract Statins inhibit cholesterol biogenesis and modulate atheroma inflammation to reduce cardiovascular risks. Promoted by immune and non-immune cells, serum C-reactive protein (CRP) might be a biomarker suboptimal to assess inflammation status. Although it has been reported that statins modulated inflammation via microRNAs (miRNAs), evidence remains lacking on comprehensive profiling of statin-induced miRNAome alterations in immune cells. We recruited 19 hypercholesterolemic patients receiving 2 mg/day pitavastatin and 15 ones receiving 10 mg/day atorvastatin treatment for 12 weeks, and performed microarray-based profiling of 1733 human mature miRNAs in peripheral blood mononuclear cells (PBMCs) before and after statin treatment. Differentially expressed miRNAs were determined if their fold changes were >1.50 or <0.67, after validated using quantitative polymerase chain reaction (qPCR). The miRSystem and miTALOS platforms were utilized for pathway analysis. Of the 34 patients aged 63.7 ± 6.2 years, 27 were male and 19 were with coronary artery disease. We discovered that statins induced differential expressions of miR-483-5p, miR-4667-5p, miR-1244, and miR-3609, with qPCR-validated fold changes of 1.74 (95% confidence interval, 1.33–2.15), 1.61 (1.25–1.98), 1.61 (1.01–2.21), and 1.68 (1.19–2.17), respectively. The fold changes of the four miRNAs were not correlated with changes of low-density-lipoprotein cholesterol or CRP, after sex, age, and statin type were adjusted. We also revealed that RhoA and transforming growth factor-β signaling pathways might be regulated by the four miRNAs. Given our findings, miRNAs might be involved in statin-induced inflammation modulation in PBMCs, providing likelihood to assess and reduce inflammation in patients with atherosclerotic cardiovascular diseases.

Platelet P-selectin facilitates atherosclerotic lesion development

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2661-2666 ◽  
Author(s):  
Peter C. Burger ◽  
Denisa D. Wagner
Keyword(s):  
Atherosclerotic Lesion ◽  
Soluble Form ◽  
Wild Type ◽  
Lesion Development ◽  
Atherosclerotic Lesions ◽  
Lesion Growth ◽  
Microparticle Formation ◽  
Apoe Deficient Mouse ◽  
Atherosclerotic Lesion Development

P-selectin is an adhesion molecule expressed on activated platelets and endothelium. It is known to play an important role in atherosclerosis. P-selectin also circulates in plasma in a soluble form (sP-selectin), which induces procoagulant microparticle formation. We investigated the role of platelet versus endothelial P-selectin in generating sP-selectin and in the formation of atherosclerotic lesions in the apolipoprotein E (apoE)–deficient mouse model. For this we transplanted apoE−/−P-selectin−/− and apoE−/−P-selectin+/+ lethally irradiated mice with bone marrow of either genotype. Seven months after transplantation, we determined from the chimeric animals that the majority of circulating sP-selectin was of endothelial origin. Thus, in atherosclerosis, the procoagulant sP-selectin reflects endothelial rather than platelet activation. We found that endothelial P-selectin was crucial for the promotion of atherosclerotic lesion growth because in its absence only relatively small lesions developed. However, platelet P-selectin also contributed to the lesion development because lesions in wild-type recipients receiving transplants with wild-type platelets were 30% larger than those receiving P-selectin-deficient platelets (P < .008) and were more frequently calcified (80% versus 44%). In comparison with P-selectin wild-type animals, absence of either endothelial or platelet P-selectin inhibited migration of smooth muscle cells into the lesion. Thus, in addition to endothelium, platelets and their P-selectin also actively promote advanced atherosclerotic lesion development.

scholarly journals Prenatal Alcohol Exposure in Rats Diminishes Postnatal Cxcl16 Chemokine Ligand Brain Expression

2020 ◽  
Vol 10 (12) ◽  
pp. 987
Author(s):  
Pedro Juárez-Rodríguez ◽  
Marisol Godínez-Rubí ◽  
Carolina Guzmán-Brambila ◽  
Edgar Padilla-Velarde ◽  
Arturo Orozco-Barocio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prenatal Alcohol Exposure ◽  
Quantitative Polymerase Chain Reaction ◽  
Alcohol Exposure ◽  
Microarray Gene Expression ◽  
Chemokine Ligand ◽  
Inflammatory Processes ◽  
Prenatal Alcohol ◽  
Rat Nucleus Accumbens ◽  
The Brain

Maternal ethanol consumption during pregnancy is one of the main causes of Neurodevelopmental disorders (NDD). Prenatal alcohol exposure (PAE) produces several adverse manifestations. Even low or moderate intake has been associated with long-lasting behavioral and cognitive impairment in offspring. In this study we examined the gene expression profile in the rat nucleus accumbens using microarrays, comparing animals exposed prenatally to ethanol and controls. Microarray gene expression showed an overall downward regulatory effect of PAE. Gene cluster analysis reveals that the gene groups most affected are related to transcription regulation, transcription factors and homeobox genes. We focus on the expression of the C-X-C motif chemokine ligand 16 (Cxcl16) which was differentially expressed. There is a significant reduction in the expression of this chemokine throughout the brain under PAE conditions, evidenced here by quantitative polymerase chain reaction qPCR and immunohistochemistry. Chemokines are involved in neuroprotection and implicated in alcohol-induced brain damage and neuroinflammation in the developing central nervous system (CNS), therefore, the significance of the overall decrease in Cxcl16 expression in the brain as a consequence of PAE may reflect a reduced ability in neuroprotection against subsequent conditions, such as excitotoxic damage, inflammatory processes or even hypoxic-ischemic insult.

scholarly journals Dietary Fruit and Vegetable Supplementation Suppresses Diet-induced Atherosclerosis in LDL Receptor Knockout Mice (OR24-07-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Weimin Guo ◽  
Sharon Kim ◽  
Dayong Wu ◽  
Lijun Li ◽  
Michael Thomas ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Knockout Mice ◽  
Agricultural Research ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Plasma Lipid ◽  
Aortic Lesion ◽  
Freeze Dried ◽  
Underlying Mechanisms ◽  
Ldl Receptor Knockout Mice

Abstract Objectives Epidemiological studies have shown that consumption of fruits and vegetables (F&V) is inversely associated with incidence of cardiovascular disease (CVD). However, the evidence for causality and underlying mechanisms is lacking. Our objective was to determine if increased consumption of F&V could prevent atherosclerosis and its underlying mechanisms. Methods A unique blend of the most commonly consumed 24 F&V was freeze-dried into a powder and mixed into diets. Thirty six 4-week old male LDL receptor knockout mice were randomly assigned to one of 3 diet groups (12/group): low fat (LF, 10 kcal% fat), high-fat (27 kcal% fat) with 0% F&V (HF), and HF plus 15% F&V diet (HF + FV, equivalent to 8–9 servings for humans). After 20 weeks, mice were euthanized and blood, aorta, and liver tissue were collected. Aortic atherosclerotic lesion, hepatic steatosis, plasma lipid profile and pro-inflammatory cytokine levels were measured. Results No significant differences were found in body weight among the 3 groups. Mice fed HF diet had larger aortic atherosclerotic lesion and hepatic steatosis area than mice fed LF diet by 6.5 and 1.9 fold, respectively (p < 0.001). HF + FV group had 80% less aortic lesion and hepatic steatosis than HF group (p < 0.001). Mice fed HF diet had significantly higher plasma TG and LDL and lower HDL levels than mice fed LF diet, and this dyslipidemia was prevented by F&V supplementation. Further, HF + FV group had lower plasma TNFα levels compared to HF0 group (p < 0.05). Spearman correlation analysis showed that aortic atherosclerotic lesion and hepatic steatosis area were negatively correlated with plasma HDL (p < 0.001) and significantly and positively correlated with TNFα, and the ratios of LDL/HDL, TG/HDL, and non HDL/HDL. Conclusions Our results demonstrate a causal role of high intake of F&V in preventing HF-induced atherosclerosis and hepatic steatosis, which may be mediated through improved dyslipidemia and reduced inflammation. Funding Sources U.S. Department of Agriculture – Agricultural Research Service. Supporting Tables, Images and/or Graphs

scholarly journals Simulation of atherosclerotic plaque growth using computational biomechanics and patient-specific data

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Dimitrios S. Pleouras ◽  
Antonis I. Sakellarios ◽  
Panagiota Tsompou ◽  
Vassiliki Kigka ◽  
Savvas Kyriakidis ◽  
...  
Keyword(s):  
Disease Progression ◽  
Plaque Burden ◽  
Patient Specific ◽  
High Density Lipoproteins ◽  
Computational Biomechanics ◽  
Plaque Area ◽  
Causes Of Mortality ◽  
Plaque Growth ◽  
Atherosclerotic Process ◽  
The One

Abstract Atherosclerosis is the one of the major causes of mortality worldwide, urging the need for prevention strategies. In this work, a novel computational model is developed, which is used for simulation of plaque growth to 94 realistic 3D reconstructed coronary arteries. This model considers several factors of the atherosclerotic process even mechanical factors such as the effect of endothelial shear stress, responsible for the initiation of atherosclerosis, and biological factors such as the accumulation of low and high density lipoproteins (LDL and HDL), monocytes, macrophages, cytokines, nitric oxide and formation of foams cells or proliferation of contractile and synthetic smooth muscle cells (SMCs). The model is validated using the serial imaging of CTCA comparing the simulated geometries with the real follow-up arteries. Additionally, we examine the predictive capability of the model to identify regions prone of disease progression. The results presented good correlation between the simulated lumen area (P < 0.0001), plaque area (P < 0.0001) and plaque burden (P < 0.0001) with the realistic ones. Finally, disease progression is achieved with 80% accuracy with many of the computational results being independent predictors.

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