Atherosclerotic plaque instability in carotid arteries: miR-200c as a promising biomarker

2018 ◽  
Vol 132 (22) ◽  
pp. 2423-2436 ◽  
Author(s):  
Alessandra Magenta ◽  
Sara Sileno ◽  
Marco D’Agostino ◽  
Francesca Persiani ◽  
Sara Beji ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Atherosclerotic Plaque ◽  
Early Recognition ◽  
Monocyte Chemoattractant Protein 1 ◽  
Carotid Plaques ◽  
Plaque Instability ◽  
Atherosclerosis Progression ◽  
E Box ◽  
Unstable Plaques ◽  
Endothelial Nitric Oxide

Early recognition of vulnerable carotid plaques could help in identifying patients at high stroke risk, who may benefit from earlier revascularisation. Nowadays, different biomarkers of plaque instability have been unravelled, among these miRNAs are promising tools for the diagnosis and treatment of atherosclerosis. Inflammation, reactive oxygen species (ROS) and endothelial dysfunction play a key role in unstable plaques genesis. We showed that miR-200c induces endothelial dysfunction, ROS production and a positive mechanism among miR-200c and miR-33a/b, two miRNAs involved in atherosclerosis progression. The goal of the present study was to determine whether miR-200c could be an atherosclerosis biomarker. Carotid plaques of patients that underwent carotid endarterectomy (CEA) were assayed for miR-200c expression. miR-200c was up-regulated in carotid plaques (n=22) and its expression was higher in unstable (n=12) compared with stable (n=10) plaques. miR-200c positively correlated with instability biomarkers (i.e. monocyte chemoattractant protein-1, cicloxigenase-2 (COX2), interleukin 6 (IL6), metalloproteinase (MMP) 1 (MMP1), 9 (MMP9)) and miR-33a/b. Moreover, miR-200c negatively correlated with stability biomarkers (i.e. zinc finger E-box binding homoeobox 1 (ZEB1), endothelial nitric oxide (NO) synthase (eNOS), forkhead boxO1 (FOXO1) and Sirtuin1 (SIRT1)) (stable plaques = 15, unstable plaques = 15). Circulating miR-200c was up-regulated before CEA in 24 patients, correlated with miR-33a/b and decreased 1 day after CEA. Interestingly, 1 month after CEA, circulating miR-200c is low in patients with stable plaques (n=11) and increased to control levels, in patients with unstable plaques (n=13). Further studies are needed to establish whether miR-200c represents a circulating biomarker of plaque instability. Our results show that miR-200c is an atherosclerotic plaque progression biomarker and suggest that it may be clinically useful to identify patients at high embolic risk.

Macrophage Infiltration and Smooth Muscle Cells Content Associated With Haptoglobin Genotype in Human Atherosclerotic Carotid Plaques

Angiology ◽  
2011 ◽  
Vol 63 (3) ◽  
pp. 178-183 ◽  
Author(s):  
Christos Lioupis ◽  
Calypso Barbatis ◽  
Paraskevi Lazari ◽  
Nikolaos Liasis ◽  
Christos Klonaris ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Atherosclerotic Plaque ◽  
Immunohistochemical Study ◽  
Macrophage Infiltration ◽  
Diabetic Patients ◽  
Serial Sections ◽  
Carotid Plaques ◽  
Plaque Instability ◽  
Haptoglobin Genotype ◽  
Patients With Diabetes

We assessed the association between the haptoglobin (Hp) genotype and 2 common indicators of atherosclerotic plaque instability: macrophage infiltration and the smooth muscle cell (SMC) content. A total of 70 consecutive patients who underwent carotid endarterectomy were included in the study. For immunohistochemical study the anti-CD68 and anti-a-actin antibodies were used on adjacent serial sections; 36 plaques from patients with the Hp 1-1 or 2-1 genotype and 34 plaques from patients with the Hp 2-2 genotype were analyzed. The macrophage content (CD68+) was significantly higher in the Hp 2-2 group compared with that in the Hp 1-1 or 2-1 group ( P < .001). In plaques from patients with diabetes, the SMC content was significantly lower in the Hp 2-2 group ( P = .034). Carotid plaques from diabetic patients with Hp 2-2 genotype had higher macrophage infiltration and lower SMC content. Both parameters are indicators of atherosclerotic plaque instability.

scholarly journals Evaluation of Serum Biomarkers for Patients at Increased Risk of Stroke

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Pelisek Jaroslav ◽  
Reeps Christian ◽  
Ockert Stefan ◽  
Zimmermann Alexander ◽  
Peter Zepper ◽  
...  
Keyword(s):  
Early Recognition ◽  
Serum Levels ◽  
Operating Characteristics ◽  
Plaque Instability ◽  
Asymptomatic Patients ◽  
Score Analysis ◽  
Increased Risk ◽  
Biomarker Analysis ◽  
Multiple Receiver ◽  
Unstable Plaques

Early recognition of vulnerable patients is an important issue for stroke prevention. In our study, a multiscore analysis of various biomarkers was performed to evaluate its superiority over the analysis of single factors. Study subjects () were divided into four groups: asymptomatic patients with stable () and unstable () plaques and symptomatic patients with stable () and unstable () plaques. Serum levels of MMP-1, -2, -3, -7, -8, -9, TIMP-1, -2, TNF-α, IL-1b, and IL-6, -8, -10, -12 were measured. Multi-score analysis was performed using multiple receiver operating characteristics (ROC) and determination of appropriate cutoff values. Significant differences between the groups were observed for MMP-1, -7, -9 and TIMP-1 in serum of the study subjects (). Multiple biomarker analysis led to a significant increase in the AUC (area under curve). In case of plaque instability, positive predictive value (PPV) for up to 86.4% could be correctly associated with vulnerable plaques. Thus, multiscore analysis might be preferable than the use of single biomarkers.

P4610Gut microbiome and atherosclerotic plaque instability: does choline consumption in red meat influence plaque stability?

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y.-C Chen ◽  
V Doma ◽  
R Reimark ◽  
Y.-L Ying ◽  
K Peter
Keyword(s):  
Atherosclerotic Plaque ◽  
High Fat Diet ◽  
Red Meat ◽  
T Test ◽  
Plaque Burden ◽  
High Fat ◽  
Plaque Instability ◽  
Choline Group ◽  
Choline Intake ◽  
Unstable Plaques

Abstract Background Myocardial infarction is the major cause of deaths worldwide. Gut bacteria can process choline as abundant in red meat and subsequently converted by flavin containing monooxygenase in the liver to trimethylamin-N-oxide (TMAO) metabolite, which is strongly associated with cardiovascular events. Aim To investigate the gut microbiome and its association with atherosclerotic plaque instability. Methods Forty-eight Apolipoprotein E deficient mice were randomly divided into two groups and two time points, fed with a high fat diet (containing either 0.4% choline or 3% choline) at 12 weeks of age, for 7 weeks or for 14 weeks. All mice underwent Tandem Stenosis (TS) surgery to induce the development of unstable plaques. Stool samples were collected directly from the colon. Measurements of gut microbes were performed by AGRF diversity profiling. After bacterial genomic DNA isolation, 16S rRNA were sequenced by targeting 27F-519R (V1-V3) and 341F-806R (V3-V4) on the Illumina MiSeq platform. Vessel segments of TS were histologically processed and plaque composition of lipid, collagen, and intraplaque hemorrhage (marker of unstable plaques) were performed by a series of chemical staining and immunohistochemistry. Results Monocytes and granulocytes in mouse blood were significantly increased in the high choline group (p<0.05, unpaired t-test) after 7 weeks of high fat diet (21% fat, 0.15% Cholesterol, 3% Choline). Profiling of gut microbiota showed that Fimicutes were down regulated in the high choline group (p<0.05, unpaired t-test). Within Phylum Fimicutes, only Clostridia (class) Clostridiales (order) were significantly downregulated. Interestingly, histological analysis of TS segments showed that TER-119 (intraplaque haemorrhage marker) and CD42c (platelet marker) were significantly increased in the high choline group, indicating atherosclerotic plaques are more unstable and prone to rupture (p<0.05, unpaired t-test). Nevertheless, CD68 (Foam cells) in plaques, and total atherosclerotic plaque burden in the aortic sinus and aortic arch were not affected by the elevated levels of choline consumption. Conclusion Choline intake increases circulating monocytes and granulocyte numbers in the blood but not in the atherosclerotic plaque itself. Whereas the total plaque burden is not changed by an increased choline intake, the reduction of Fimicutes, Clostridia and Clostridiales seems to contribute to atherosclerotic plaque instability. Acknowledgement/Funding Heart Foundation 2018 Future Leader Fellowship (2018 FLF) ID: 102068 Chen

scholarly journals Features of atherosclerosis in carotid and coronary arteries

2021 ◽  
pp. 44-53
Author(s):  
E. V. Konstantinova ◽  
A. A. Bogdanova ◽  
A. A. Sagatelyan ◽  
A. I. Kovaikin ◽  
E. S. Pershina ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Atherosclerotic Plaque ◽  
Circulatory System ◽  
Coronary Vessels ◽  
Mortality And Morbidity ◽  
Plaque Instability ◽  
Effective Interventions ◽  
Inflammatory Processes ◽  
Unstable Plaques ◽  
Plaque Destabilization

Atherothrombosis is a leading cause of myocardial infarction and ischemic atherothrombotic stroke. It represents a stage of atherosclerosis which is a pathologic process throughout the circulatory system. However, atherosclerosis has specific development characteristics in  different vascular beds. Multiple factors contribute to atherosclerosis formation and progression such as genetic factors, vessel hemodynamics, and vessel anatomy. A better understanding of differences in vessels would improve prevention and treatment of atherosclerosis and its complication. In this article we review features of atherosclerosis in carotid and coronary vessels. We discuss specific conditions of local hemodynamics in the areas of bifurcation which promote atherosclerotic plaque progression, and review characteristics of unstable plaques in carotid and coronary vessels. We analyze immunologic and inflammatory processes, extracellular matrix degradation and remodeling, cellular apoptosis and autophagy occurring during atherosclerotic plaque destabilization as well as the possibility of diffuse plaque instability in systemic atherosclerosis. We review association and interaction of  atherosclerotic processes in  coronary and carotid arteries, and its significance for a patient. Improvement in understanding of atherosclerosis pathogenesis can lead to advances in atherosclerosis prevention. Timely and effective interventions would promote prevention of myocardial infarction and ischemic stroke which is highly important taking into account high mortality and morbidity rates.

scholarly journals Expression of Resistin, Chemerin, and Chemerin’s Receptor in the Unstable Carotid Atherosclerotic Plaque

Stroke ◽  
2021 ◽  
Author(s):  
Russell Yanofsky ◽  
Carina Sancho ◽  
Karina Gasbarrino ◽  
Huaien Zheng ◽  
Robert J. Doonan ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Atherosclerotic Plaque ◽  
Carotid Plaque ◽  
Carotid Atherosclerosis ◽  
Staining Intensity ◽  
Carotid Atherosclerotic Plaque ◽  
Carotid Plaques ◽  
Plaque Instability ◽  
The Relationship

Background and Purpose: Unstable carotid plaques are a common cause of ischemic strokes. Identifying markers that reflect/contribute to plaque instability has become a prominent focus in cardiovascular research. The adipokines, resistin and chemerin, and ChemR23 (chemerin receptor), may play a role in carotid atherosclerosis, making them potential candidates to assess plaque instability. However, the expression and interrelationship of resistin and chemerin (and ChemR23) protein and mRNA within the carotid atherosclerotic plaque remains elusive. Thus, we investigated herein, the association between plaque mRNA and protein expression of resistin and chemerin (and ChemR23) and carotid plaque instability in humans, and whether sex differences exist in the relationship between these adipokines and plaque instability. Methods: Human carotid plaques were processed for immunohistochemical/mRNA analysis of resistin, chemerin, and ChemR23. Plaque instability was assessed by gold-standard histological classifications. A semi-quantitative scoring system was used to determine the intensity of adipokine expression on macrophages/foam cells, as well as the percentage of inflammatory cells stained positive. Plaque adipokine protein expression was also digitally quantified and mRNA expression was assessed by qRT-PCR. Results: Resistin and chemerin mRNA expression was 80% and 32% lower, respectively, in unstable versus stable plaques ( P <0.05), while no difference in ChemR23 mRNA expression was observed. In contrast, greater resistin staining intensity and percentage of cells stained positive were detected in unstable versus stable plaques ( P <0.01). Similarly, chemerin and ChemR23 staining intensity and percentage of cells stained were positively associated with plaque instability ( P <0.05). No strong sex-specific relationship was observed between adipokines and plaque instability. Conclusions: This study examined the relationship between resistin, chemerin, and ChemR23, and carotid plaque instability, with a specific analysis at the plaque level. We reported a positive association between plaque instability and protein levels of resistin, chemerin, and ChemR23 but a negative association with resistin and chemerin mRNA expression. This suggests these adipokines exert proinflammatory roles in the process of carotid atherosclerosis and may be regulated via a negative feedback regulatory mechanism.

Oxidation and Endothelial Dysfunction Biomarkers of Atherosclerotic Plaque Instability. Studies of the Vascular Wall and Blood

2012 ◽  
Vol 153 (3) ◽  
pp. 331-335 ◽  
Author(s):  
Yu. I. Ragino ◽  
A. M. Chernjavski ◽  
Ya. V. Polonskaya ◽  
A. M. Volkov ◽  
E. V. Kashtanova ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Atherosclerotic Plaque ◽  
Vascular Wall ◽  
Plaque Instability

Abstract 591: Leptin receptor long Isoform is Increased and Positively Correlated with Augmented Macrophage Infiltration and Plaque Neovascularization in Carotid Plaques from Neurologically Symptomatic Patients

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jacob Schneiderman ◽  
Amos J Simon ◽  
Marco R Schroeter ◽  
Isaac Engelberg ◽  
Moshe Y Flugelman ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Inflammatory Cells ◽  
Macrophage Infiltration ◽  
Pcr Analysis ◽  
Systematic Analysis ◽  
Carotid Plaques ◽  
Plaque Instability ◽  
Symptomatic Carotid ◽  
Macrophage Density ◽  
Unstable Plaques

Objectives: Symptomatic carotid plaques are frequently characterized by increased inflammation and neovascularization. As leptin promotes plaque angiogenesis and activates inflammatory cells, and since the leptin receptor (ObR) antigen was demonstrated in advanced atherosclerotic plaques, we undertook a systematic analysis of carotid symptomatic and asymptomatic plaques, quantitatively assessing ObR mRNA expression and immunoreactivity. Moreover, parallel analyses of VEGF 165 , and Mac-1 transcript were performed, to account for plaque angiogenesis and macrophage density , respectively. Methods: Carotid endarterectomy (CEA) plaques were collected from 26 patients undergoing surgery for hemispheric cerebro-vascular symptoms (13), or progressive asymptomatic internal carotid stenosis (13). A representative sample collected from each plaque was used in real-time quantitative (RQ) PCR analysis for ObRl (long), ObRc (common) isoforms, VEGF 165 , and Mac-1 transcripts. All plaques were classified histologically according to the AHA guidelines. Also, immunohistochemistry for von Willebrand factor (vWF) and ObR antigen were performed. Results: All plaques exhibited advanced atherosclerosis, and AHA class V through VI were equally diagnosed in both groups. Interestingly, ObRl transcript levels were preferentially elevated in symptomatic plaques (P<0.03). A similar upregulation was demonstrated for VEGF 165 (P<0.017), and Mac-1 (P<0.013). Immunohistochemical analyses also demonstrated that ObR antigen was significantly augmented in symptomatic plaques (P<0.05), and frequently colocalized with abundance of inflammatory cells. Neovascularization was evident in all plaques, and marginally increased in symptomatic plaques. Conclusions: ObR-1 gene is preferentially upregulated, in clinically symptomatic carotid plaques, and positively correlated with simultaneous augmentation of VEGF 165 and Mac-1 transcript. These data suggest that ObR-1 may be linked with histological features of plaque instability, like neovascularization and macrophage infiltration, shown to be associated with ischemic symptoms from carotid unstable plaques.

Abstract TP110: Helicobacter Pylori Infection and Genetic Factors as Determinants of Carotid Plaque Stability

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Eugenia Arias ◽  
Naomi Arakaki ◽  
Horacio Martinetto ◽  
Gustavo E Sevlever ◽  
Sebastian F Ameriso
Keyword(s):  
Inflammatory Cells ◽  
Exact Test ◽  
Carotid Plaques ◽  
Plaque Instability ◽  
Asymptomatic Patients ◽  
Human Atherosclerosis ◽  
Unstable Plaques ◽  
H Pylori ◽  
Asymptomatic Subjects

Introduction: Little is known about the role of H pylori in human atherosclerosis. We have previously demonstrated its presence in carotid plaques, especially among asymptomatic patients, with prevalence of cag A-positive strains. Polymorphisms of genes of angiotensin-converting enzyme (ACE), lipoprotein APOE (APOE), IL1 receptor antagonist (IL1Ra) and myeloperoxidase (MPO) are associated with atherosclerosis. We evaluated the role of H pylori in certain features of carotid plaques and assessed allelic and genotypic frequencies and their association with H pylori infection and plaque characteristics. Methods: We studied 137 carotid plaques of patients undergoing endarterectomy. We categorized as stable those predominantly fibrous plaques with scarce inflammatory cells, intact cap and no hemorrhage and unstable those plaques with inflammation, thin cap, ruptured lipid core, thrombi and hemorrhage. We extracted genomic DNA and identified and typified H Pylori DNA. DNA was also obtained from peripheral blood and we identified allelic and genotypic frequencies and susceptibility variants of ACE, APOE, IL1Ra, and MPO genes. Fisher’s exact test (two-tailed) and good fit test were used. Results: There were 72 asymptomatic patients with 47 stable and 25 unstable plaques and 65 symptomatic patients with 13 stable and 52 unstable plaques (p<0.0001). H pylori infection was present in 48 of 60 stable plaques and 31 of 77 unstable plaques (p<0.0001). In addition, stable infected plaques more often carried the more virulent cag A strain. H pylori cag A-negative plaques had larger intima media complex thickness than cag A-positive and H pylori -negative plaques. Stable infected plaques were associated to alleles APOE-33 and IL1RN-11. Unstable noninfected plaques were associated to proatherogenic alleles ACE-DD, APOE*4, APOE*2, IL1RN*2, and MPO-GG. Conclusions: Histopathological features of plaque instability are associated to the presence of recent symptoms. H pylor i infection with the virulent cag A strain is highly prevalent in stable carotid plaques of asymptomatic subjects. Noninflammatory genotypes are present in stable infected plaques whereas proatherogenic polymorphisms are predominant in unstable noninfected plaques.

scholarly journals Regulation of miRNAs by Natural Antioxidants in Cardiovascular Diseases: Focus on SIRT1 and eNOS

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 377
Author(s):  
Yunna Lee ◽  
Eunok Im
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Natural Antioxidants ◽  
Sirtuin 1 ◽  
Potential Benefits ◽  
New Perspective ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Cardiovascular diseases (CVDs) are the most common cause of morbidity and mortality worldwide. The potential benefits of natural antioxidants derived from supplemental nutrients against CVDs are well known. Remarkably, natural antioxidants exert cardioprotective effects by reducing oxidative stress, increasing vasodilation, and normalizing endothelial dysfunction. Recently, considerable evidence has highlighted an important role played by the synergistic interaction between endothelial nitric oxide synthase (eNOS) and sirtuin 1 (SIRT1) in the maintenance of endothelial function. To provide a new perspective on the role of natural antioxidants against CVDs, we focused on microRNAs (miRNAs), which are important posttranscriptional modulators in human diseases. Several miRNAs are regulated via the consumption of natural antioxidants and are related to the regulation of oxidative stress by targeting eNOS and/or SIRT1. In this review, we have discussed the specific molecular regulation of eNOS/SIRT1-related endothelial dysfunction and its contribution to CVD pathologies; furthermore, we selected nine different miRNAs that target the expression of eNOS and SIRT1 in CVDs. Additionally, we have summarized the alteration of miRNA expression and regulation of activities of miRNA through natural antioxidant consumption.

scholarly journals Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress

2016 ◽  
Vol 310 (1) ◽  
pp. H39-H48 ◽  
Author(s):  
Masashi Mukohda ◽  
Madeliene Stump ◽  
Pimonrat Ketsawatsomkron ◽  
Chunyan Hu ◽  
Frederick W. Quelle ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Nitric Oxide Synthase ◽  
Transgenic Mice ◽  
Stress Responses ◽  
Endothelial Nitric Oxide Synthase ◽  
Ppar Γ ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Loss of peroxisome proliferator-activated receptor (PPAR)-γ function in the vascular endothelium enhances atherosclerosis and NF-κB target gene expression in high-fat diet-fed apolipoprotein E-deficient mice. The mechanisms by which endothelial PPAR-γ regulates inflammatory responses and protects against atherosclerosis remain unclear. To assess functional interactions between PPAR-γ and inflammation, we used a model of IL-1β-induced aortic dysfunction in transgenic mice with endothelium-specific overexpression of either wild-type (E-WT) or dominant negative PPAR-γ (E-V290M). IL-1β dose dependently decreased IκB-α, increased phospho-p65, and increased luciferase activity in the aorta of NF-κB-LUC transgenic mice. IL-1β also dose dependently reduced endothelial-dependent relaxation by ACh. The loss of ACh responsiveness was partially improved by pretreatment of the vessels with the PPAR-γ agonist rosiglitazone or in E-WT. Conversely, IL-1β-induced endothelial dysfunction was worsened in the aorta from E-V290M mice. Although IL-1β increased the expression of NF-κB target genes, NF-κB p65 inhibitor did not alleviate endothelial dysfunction induced by IL-1β. Tempol, a SOD mimetic, partially restored ACh responsiveness in the IL-1β-treated aorta. Notably, tempol only modestly improved protection in the E-WT aorta but had an increased protective effect in the E-V290M aorta compared with the aorta from nontransgenic mice, suggesting that PPAR-γ-mediated protection involves antioxidant effects. IL-1β increased ROS and decreased the phospho-endothelial nitric oxide synthase (Ser1177)-to-endothelial nitric oxide synthase ratio in the nontransgenic aorta. These effects were completely abolished in the aorta with endothelial overexpression of WT PPAR-γ but were worsened in the aorta with E-V290M even in the absence of IL-1β. We conclude that PPAR-γ protects against IL-1β-mediated endothelial dysfunction through a reduction of oxidative stress responses but not by blunting IL-1β-mediated NF-κB activity.

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