Abstract 511: Mrp8 And Mrp14,Endogenous Activators of Toll-lLke Receptor4, are Associated with Rupture-Prone Human Atherosclerotic Plaques

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mihaela G Ionita ◽  
Gerard Pasterkamp ◽  
Dominique deKleijn
Keyword(s):  
Atherosclerotic Plaque ◽  
Atherosclerotic Plaques ◽  
Atherosclerotic Lesions ◽  
Inflammatory Status ◽  
Potential Marker ◽  
Plaque Phenotype ◽  
Histological Characteristics ◽  
Unstable Plaques ◽  
Human Carotid

Objectives : Atherosclerosis is a chronic, complex inflammatory process and is the underlying cause of stroke and myocardial infarction due to rupture of the atherosclerotic plaque leading to acute occlusion of the artery in the brain or heart. Macrophages, infiltrating atherosclerotic lesions, abundantly express Mrp8 and Mrp14. Recently Mrp8, Mrp14 and the complex Mrp8/14 have been identified as endogenous ligands of Tlr-4.The role of Tlr-4 in the development and progression of the atherosclerotic plaque is well recognized and it is associated with a rupture-prone plaque phenotype. Expression of Mrps in human plaques and its relation to plaque phenotype is unknown. For this, we investigated the levels of Mrp8, Mrp14 and Mrp8/14 complex in a large number of human atherosclerotic plaques. Methods and results : Mrp8, Mrp14 and Mrp8/14 were quantified by ELISAs in human carotid endarterectomy specimens (186 patients) and plaque phenotype was determined by immunohistochemistry. Mrp levels were higher in the unstable (58 fibro-atheromatous, 64 atheromatous) compared to the stable (64 fibrous) plaques: Mrp8 p = 0.001 ; Mrp14 p = 0.001 ; Mrp8/14 p = 0.01 . Concomitantly, Mrp8, Mrp14 and Mrp8/14 were associated with characteristics of unstable plaques: more macrophages ( p = 0.024; p = 0.002; p = 0.076 ), less smooth muscle cells ( p = 0.041; p = 0.001; p = 0.074 ), larger lipid core ( p = 0.001; p = 0.001; p=0.004 ), less collagen ( p = 0.440; p = 0.011; p = 0.372 ). Furthermore, Mrp plaque levels were positively correlated with the pro-inflammatory cytokines (IL-6 and IL-8) and matrix metalloproteinsases (MMP2, MMP8 and MMP9) plaque levels. EDA, marker of stable plaques, was negatively associated with Mrps plaque levels. Histological analysis revealed that Mrps are expressed by a subgroup of plaque macrophages localized in the plaque cap and shoulder, the most rupture-prone sites of an atherosclerotic plaque. Conclusions: We show that Mrp8, Mrp14 and Mrp8/14 are strongly associated with the histological characteristics and inflammatory status of human rupture-prone plaques and identify Mrps as a potential marker for rupture-prone plaques.

Abstract 340: The Expression and Function of Apol6 in Atherosclerotic Plaques of Apoe -/- Mouse Aorta Tissue

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Siqin Zhaorigetu ◽  
Chien-An A Hu ◽  
Warren Laskey ◽  
Brian Walton
Keyword(s):  
Atherosclerotic Plaque ◽  
Sirna Delivery ◽  
Aortic Tissue ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
And Function ◽  
Mouse Aorta

Background: We recently demonstrated that apolipoprotein L6 (ApoL6) regulates apoptosis and autophagy in atherosclerotic lesions, implying that ApoL6 is an important factor that causes plaque instability and a potential therapeutic target for treating atherosclerosis. To further investigate the role of ApoL6 in atherogenesis in vivo , the expression of ApoL6 was knocked down by the liposome-siRNA strategy in the aorta tissue of ApoE -/- mouse. Methods: Liposomal siRNAs were prepared by using the thin-film hydration method and were labeled with quantum dots (QD). ApoE -/- mice were intravenously injected twice in 1 week with either liposomal control siRNA-QD or liposomal ApoL6 siRNA-QD. We harvested aortic tissue from mice and used immunofluorescence staining to analyze the expression of ApoL6 in atherosclerotic plaque. Results: Immunofluorescence analysis showed that expression of ApoL6 was elevated in the atherosclerotic plaque and partially co-localized with a macrophage marker CD68 in ApoE -/- mouse. The results suggest a link between ApoL6 and macrophages in the pathobiology of atherosclerotic lesions ( Fig. A and B ). Confocal microscopy images showed that liposomal ApoL6 siRNA significantly reduced ApoL6 expression (green punctures) in atherosclerotic plaques as compared with liposomal control siRNA (Fig. C) . Conclusion: We established a silencing model of ApoL6 in cardiovascular system of ApoE -/- mouse using liposome-mediated siRNA delivery system. The intravenous injection of liposomal ApoL6 siRNA silences ApoL6 expression in the aortas of ApoE -/- mice and may protect against the development of atherosclerosis.

scholarly journals The role of cell proliferation in atherogenesis and in the destabilization of atherosclerotic plaque in human

2019 ◽  
Vol 19 (2) ◽  
pp. 7-12
Author(s):  
Peter V. Pigarevsky ◽  
Olga G. Yakovleva ◽  
Svetlana V. Maltseva ◽  
Veronica A. Guseva
Keyword(s):  
Cell Proliferation ◽  
Atherosclerotic Plaque ◽  
Vascular Wall ◽  
Original Data ◽  
Atherosclerotic Plaques ◽  
Proliferating Cells ◽  
Experimental Animals ◽  
Atherosclerotic Lesions

The review examined of the processes of cell proliferation in human vascular wall and experimental animals during the formation of atherosclerotic plaques. Shows the types of actively proliferating cells: lymphocytes, macrophages, endotheliocytes and zones identified in the vascular wall, where this proliferation occurs. The factors that promote and hinder cell proliferation during the growth of atherosclerotic plaque are identified. The survey shows all the stages of the formation of atherosclerotic lesions, ranging from normal plots and lipid stains to pronounced fibrous plaques. Establishes a link between the cell proliferation and inflammation in the vascular wall man. Separately considered the role of cell proliferation in the destabilization of atherosclerotic plaque. If atherosclerosis this process still poorly studied, in the formation of unstable atherosclerotic plaques in humans it is completely unknown. Based on your own original data was finally on the important role of the processes of cell proliferation in the formation of unstable atherosclerotic plaques in humans.

scholarly journals Comparative immunohistochemical and morphometric research of interleukin-17 in various atherosclerotic lesions in human

2020 ◽  
Author(s):  
Petr V. Pigarevsky ◽  
Vlada A Snegova ◽  
Svetlana V. Maltseva ◽  
Natalia G. Davydova
Keyword(s):  
Atherosclerotic Plaque ◽  
Mononuclear Cells ◽  
Atherosclerotic Plaques ◽  
Interleukin 17 ◽  
Atherosclerotic Lesions ◽  
Th 17 ◽  
Unstable Atherosclerotic Plaque ◽  
First Time ◽  
Inflammatory Action

The aim of the artical to investigate cellular and tissue localization of IL-17 in various atherosclerotic lesions of arteries of human and on the basis of the obtained data to make a hypothesis of a possible role of Th-17 of cells in destabilization of an atherosclerotic plaque. Material and methods. On autopsy material by means of histologic, immunohistochemical and morphometric research techniques aorta segments, the coronary arteries and a.basilaris with various types of atherosclerotic lesions (43 samples of tissue) were studied. In samples of tissue studied the endothelial and mononuclear cells expressing interleukin-17. Results. It is shown that endothelial cells of an intima are capable to produce IL-17 in all types of atherosclerotic plaques. Increase in number of the mononuclear cells expressing IL-17 in an intima of arteries was at the same time revealed. It is shown that the maximum number of the cells expressing IL-17 was found in an intima of an unstable atherosclerotic plaque, it is especially frequent around a rupture of its cap. What can demonstrate pro-inflammatory action of Th - 17 - cells and IL-17 expressed by them and significant effect them on formation of unstable atherosclerotic lesions. Conclusion. On the basis of the obtained data for the first time it was succeeded to make a hypothesis of a possible role of Th-17 of cells in destabilization of an atherosclerotic plaque.

Expression and Cellular Localization of CXCR4 and CXCL12 in Human Carotid Atherosclerotic Plaques

2018 ◽  
Vol 118 (01) ◽  
pp. 195-206 ◽  
Author(s):  
Sophie Merckelbach ◽  
Emiel van der Vorst ◽  
Michael Kallmayer ◽  
Christoph Rischpler ◽  
Rainer Burgkart ◽  
...  
Keyword(s):  
Protein Level ◽  
Cellular Localization ◽  
Mrna Level ◽  
Plaque Morphology ◽  
Atherosclerotic Plaques ◽  
Cxcl12 Expression ◽  
Carotid Plaques ◽  
Unstable Plaques ◽  
Human Carotid

Background and Aims The CXCR4/CXCL12 complex has already been associated with progression of atherosclerosis; however, its exact role is yet unknown. The aim of this study was to analyse the expression and cellular localization of CXCL12 and its receptor CXCR4 in human carotid atherosclerotic plaques. Methods Carotid plaques (n = 58; 31 stable, 27 unstable, based on histological characterization of plaque morphology) were obtained during carotid endarterectomy, and 10 healthy vessels were used as a control. Expression of cxcr4, cxcr7, cxcl12, ccl2/ccr2 and csf1/csf1r was analysed at mRNA, and level expression of CXCR4, CXCR7 and CXCL12 was analysed at protein level. Cellular localization was determined using consecutive and double immunohistochemical (IHC) staining and microdissection. Results At mRNA level, cxcr4, cxcr7 and cxcl12 were significantly higher expressed in stable carotid plaques compared with controls (p = 0.011, p < 0.001 and p < 0.001). Cxcl12 mRNA expression was successively augmented toward unstable plaques (p < 0.001). At protein level, CXCR4, CXCR7 and CXCL12 expression was significantly increased in both stable (p = 0.001, p < 0.001 and p = 0.035, respectively) and unstable (p = 0.003, p < 0.001 and p = 0.045, respectively) plaques compared with controls. Using IHC, CXCR4 was particularly localized in macrophages and small neovessels. Microdissection confirmed strongest expression of cxcr4 in macrophages within atherosclerotic plaques. Leukocytes and smooth muscle cells showed cxcr4 expression as well. For cxcl12, only microdissected areas with macrophages were positive. Conclusion Expression of CXCR4 and CXCL12 was significantly increased in both stable and unstable carotid atherosclerotic plaques compared with healthy vessels, both at mRNA and protein level. CXCR4 and CXCL12 were localized particularly in macrophages.

In Vitro Three Dimensional Imaging of Human Carotid Atherosclerotic Plaques Using Ultrasonography

2011 ◽  
Author(s):  
Renate W. Boekhoven ◽  
Marcel C. M. Rutten ◽  
Marc R. H. M. van Sambeek ◽  
Frans N. van de Vosse
Keyword(s):  
Mechanical Properties ◽  
Carotid Artery ◽  
Carotid Endarterectomy ◽  
Early Stage ◽  
Three Dimensional ◽  
Atherosclerotic Plaques ◽  
Unstable Plaques ◽  
Human Carotid ◽  
Selection Of

Ruptured atherosclerotic plaques in the carotid artery are the main cause of stroke (70–80%). To prevent it, carotid endarterectomy is the procedure of choice in patients with a recent symptomatic 70–99% stenosis. Today, the selection of candidates is based on stenosis size only. However, endarterectomy is beneficial for only 1 out of 6 patients [1], the patients with unstable plaques (Fig. 1). Knowledge of mechanical properties of different components in the atherosclerotic arteries is important, because it will allow the identification of plaque stability at an early stage.

Comparison of two murine models of thrombosis induced by atherosclerotic plaque injury

2011 ◽  
Vol 105 (S 06) ◽  
pp. S3-S12 ◽  
Author(s):  
Béatrice Hechler ◽  
Christian Gachet
Keyword(s):  
Atherosclerotic Plaque ◽  
Plaque Rupture ◽  
Vascular Lesions ◽  
Murine Models ◽  
Atherosclerotic Lesions ◽  
Human Pathology ◽  
Rupture Model ◽  
Atherosclerotic Plaque Rupture ◽  
Collagen Receptor

SummaryArterial thrombosis occurs at sites of erosion or rupture of atherosclerotic vascular lesions. To better study the pathophysiology of this complex phenomenon, there is a need for animal models of localised thrombosis at sites of atherosclerotic lesions with closer resemblance to the human pathology as compared to commonly used thrombosis models in healthy vessels. In the present study, we describe and compare a new model of thrombosis induced by atherosclerotic plaque rupture in the carotid artery from ApoE-/- mice using a suture needle to a milder model of ultrasound-induced plaque injury. Needle injury induces atherosclerotic plaque rupture with exposure of plaque material and formation of a thrombus that is larger, nearly occlusive and more stable as compared to that formed by application of ultrasounds. These two models have common features such as the concomitant involvement of platelet activation, thrombin generation and fibrin formation, which translates into sensitivity toward both antiplatelet drugs and anticoagulants. On the other hand, they display differences with respect to the role of the platelet collagen receptor GPVI, the plaque rupture model being less sensitive to its inhibition as compared to the ultrasound-induced injury, which may be related to the amount of thrombin generated. These models represent an improvement as compared to models in healthy vessels and may help identify specific plaque triggers of thrombosis. They should therefore be useful to evaluate new antithrombotic targets.

scholarly journals Discoidin Domain-Containing Receptor 2 Is Present in Human Atherosclerotic Plaques and Involved in the Expression and Activity of MMP-2

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Qi Yu ◽  
Ruihan Liu ◽  
Ying Chen ◽  
Ahmed Bilal Waqar ◽  
Fuqiang Liu ◽  
...  
Keyword(s):  
Animal Models ◽  
Matrix Metalloproteinases ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherosclerotic Plaques ◽  
Clinical Role ◽  
Induced Expression ◽  
Unstable Plaques ◽  
Expression And Activity

Discoidin domain-containing receptor 2 (DDR2) has been suggested to be involved in atherosclerotic progression, but its pathological role remains unknown. Using immunochemical staining, we located and compared the expression of DDR2 in the atherosclerotic plaques of humans and various animal models. Then, siRNA was applied to knock down the expression of DDR2 in vascular smooth muscle cells (VSMCs), and the migration, proliferation, and collagen Ι-induced expression of matrix metalloproteinases (MMPs) were evaluated. We found that an abundance of DDR2 was present in the atherosclerotic plaques of humans and various animal models and was distributed around fatty and necrotic cores. After incubation of oxidized low-density lipoprotein (ox-LDL), DDR2 was upregulated in VSMCs in response to such a proatherosclerotic condition. Next, we found that decreased DDR2 expression in VSMCs inhibited the migration, proliferation, and collagen Ι-induced expression of matrix metalloproteinases (MMPs). Moreover, we found that DDR2 is strongly associated with the protein expression and activity of MMP-2, suggesting that DDR2 might play a role in the etiology of unstable plaques. Considering that DDR2 is present in the atherosclerotic plaques of humans and is associated with collagen Ι-induced secretion of MMP-2, the clinical role of DDR2 in cardiovascular disease should be elucidated in further experiments.

scholarly journals Ferryl Hemoglobin and Heme Induce Α1-Microglobulin in Hemorrhaged Atherosclerotic Lesions with Inhibitory Function against Hemoglobin and Lipid Oxidation

2021 ◽  
Vol 22 (13) ◽  
pp. 6668
Author(s):  
Dávid Pethő ◽  
Tamás Gáll ◽  
Zoltán Hendrik ◽  
Annamária Nagy ◽  
Lívia Beke ◽  
...  
Keyword(s):  
Radical Scavenging ◽  
Cell Types ◽  
Oxidative Modification ◽  
Atherosclerotic Plaques ◽  
Aortic Endothelial Cells ◽  
Inhibitory Function ◽  
Atherosclerotic Lesions ◽  
Atheromatous Plaques ◽  
Heme Binding Protein

Infiltration of red blood cells into atheromatous plaques and oxidation of hemoglobin (Hb) and lipoproteins are implicated in the pathogenesis of atherosclerosis. α1-microglobulin (A1M) is a radical-scavenging and heme-binding protein. In this work, we examined the origin and role of A1M in human atherosclerotic lesions. Using immunohistochemistry, we observed a significant A1M immunoreactivity in atheromas and hemorrhaged plaques of carotid arteries in smooth muscle cells (SMCs) and macrophages. The most prominent expression was detected in macrophages of organized hemorrhage. To reveal a possible inducer of A1M expression in ruptured lesions, we exposed aortic endothelial cells (ECs), SMCs and macrophages to heme, Oxy- and FerrylHb. Both heme and FerrylHb, but not OxyHb, upregulated A1M mRNA expression in all cell types. Importantly, only FerrylHb induced A1M protein secretion in aortic ECs, SMCs and macrophages. To assess the possible function of A1M in ruptured lesions, we analyzed Hb oxidation and heme-catalyzed lipid peroxidation in the presence of A1M. We showed that recombinant A1M markedly inhibited Hb oxidation and heme-driven oxidative modification of low-density lipoproteins as well plaque lipids derived from atheromas. These results demonstrate the presence of A1M in atherosclerotic plaques and suggest its induction by heme and FerrylHb in the resident cells.

scholarly journals Macrophages and Their Role in Destabilization of an Atherosclerotic Plaque

Kardiologiia ◽  
2019 ◽  
Vol 59 (4) ◽  
pp. 88-91 ◽  
Author(s):  
P. V. Pigarevsky ◽  
V. A. Snegova ◽  
P. G. Nazarov
Keyword(s):  
Cell Population ◽  
Atherosclerotic Plaque ◽  
Functional Activity ◽  
Vascular Wall ◽  
Atherosclerotic Plaques ◽  
M2 Macrophages ◽  
Main Attention ◽  
M1 Phenotype

The modern data on structure and the functional activity of macrophages are presented in the review. It is shown that they are the nonhomogeneous cell population. Two of their main subpopulations are presented as M1 and M2 phenotypes which perform opposite functions at inflammation development. The main attention in the review is paid to a role of macrophages in pathogenesis of atherosclerosis and, first, in formation of unstable atherosclerotic plaques which are the cause of the most severe complications of the disease. It is shown that main subpopulations of macrophages play different roles in formation of unstable and stable atherosclerotic plaques. Macrophages of M1 phenotype in the vascular wall carry out pro-atherogenic role and influence destabilization of an atherosclerotic plaque, while M2 macrophages perform atheroprotective function.

scholarly journals An investigation into the critical role of fibre orientation in the ultimate tensile strength and stiffness of human carotid plaque caps

2020 ◽  
Author(s):  
R.D. Johnston ◽  
R.T. Gaul ◽  
C. Lally
Keyword(s):  
Atherosclerotic Plaque ◽  
Critical Role ◽  
Experimental Studies ◽  
Atherosclerotic Lesion ◽  
Collagen Fibre ◽  
Atherosclerotic Plaques ◽  
Fibrous Plaque ◽  
Carotid Plaques ◽  
Risk Of Rupture ◽  
Human Carotid

AbstractThe development and subsequent rupture of atherosclerotic plaques in human carotid arteries is a major cause of ischemic stroke. Mechanical characterization of atherosclerotic plaques can aid our understanding of this rupture risk. Despite this however, experimental studies on human atherosclerotic carotid plaques, and fibrous plaque caps in particular, are very limited. This study aims to provide further insights into atherosclerotic plaque rupture by mechanically testing human fibrous plaque caps, the region of the atherosclerotic lesion most often attributed the highest risk of rupture. The results obtained highlight the variability in the ultimate tensile stress, strain and stiffness experienced in atherosclerotic plaque caps. By pre-screening all samples using small angle light scattering (SALS) to determine the dominant fibre direction in the tissue, along with supporting histological analysis, this work suggests that the collagen fibre alignment in the circumferential direction plays the most dominant role for determining plaque structural stability. The work presented in this study could provide the basis for new diagnostic approaches to be developed, which non-invasively identify carotid plaques at greatest risk of rupture.Graphical Abstract

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