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.

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.

Abstract 380: Vascular Pcsk9: A Mediator for Atherogenesis Independent of LDL Receptor

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hua Sun ◽  
Michael Tan ◽  
Ba-bie Teng
Keyword(s):  
Endothelial Cells ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Degradation Process ◽  
Double Knockout ◽  
Aortic Endothelial Cells ◽  
Apob Mrna ◽  
Pcsk9 Gene ◽  
Atherosclerotic Lesions

PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases the LDL levels by binding to hepatocyte LDL receptors (LDLR) and subjects it to degradation. We show that PCSK9 regulates apolipoprotein B (apoB) production by inhibiting its degradation process via the autophagic pathway, irrespective of the presence of LDLR. In addition to the role of PCSK9 in promoting hyperlipidemia, we hypothesized that vascular-PCSK9 in endothelial cells (EC) plays a role in initiating atherogenesis, irrespective of the presence of LDL receptor. Our laboratory has generated double knockout mice lacking both LDLR and Apobec1 (apoB mRNA editing enzyme), named LDb, Ldlr-/-Apobec1-/-. They have the lipoprotein phenotype mimics human with hyperlipidemia; elevated levels of VLDL and LDL with low levels of HDL. They develop atherosclerotic lesions spontaneously. To investigate the role of PCSK9 in atherogenesis, we deleted Pcsk9 gene from LDb mice to generate the triple knockout mice (named LTp, Ldlr-/-Apobec1-/-Pcsk9-/-). In comparison to LDb mice (n=14), the LTp mice (n=8) had significantly decreased levels of cholesterol (387±10 vs. 313±14 mg/dl; p<0.0008) and triglyceride (304±15 vs. 204±2.3 mg/dl; p<0.0002). However, despite their high cholesterol levels at over 300 mg/dl, the atherosclerotic lesions in LTp mice were significantly decreased in comparison to LDb mice (8.8%±3.5 vs. 24%±3.3, p=0.004, n=5 vs. 5). We hypothesized that vascular PCSK9 regulates the development of atherosclerosis. We incubated LDL containing PCSK9 (LDL/PCSK9) on primary aortic endothelial cells (EC) obtained from LDb or LTp to study the effects of LDL/PCSK9 on inflammation. We show that LDL/PCSK9 could not induce the expressions of Lox-1, TLR-2, or ICAM-1 in EC from LTp, resulting in absence responses on proinflammatory markers (CCL2 and CCL7) and autophagic molecules (p62 and TRAF6). In conclusion, our results suggest that vascular PCSK9 play an essential role in atherogenesis.

scholarly journals Mitochondrion as a Selective Target for the Treatment of Atherosclerosis: Role of Mitochondrial DNA Mutations and Defective Mitophagy in the Pathogenesis of Atherosclerosis and Chronic Inflammation

2020 ◽  
Vol 18 (11) ◽  
pp. 1064-1075 ◽  
Author(s):  
Alexander N. Orekhov ◽  
Anastasia V. Poznyak ◽  
Igor A. Sobenin ◽  
Nikita N. Nikifirov ◽  
Ekaterina A. Ivanova
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Chronic Inflammation ◽  
Cell Types ◽  
Neurological Complications ◽  
Atherosclerotic Plaques ◽  
Mtdna Mutations ◽  
Disease Markers ◽  
Chronic Inflammatory Condition

Background: Atherosclerosis is a chronic inflammatory condition that affects different arteries in the human body and often leads to severe neurological complications, such as stroke and its sequelae. Affected blood vessels develop atherosclerotic lesions in the form of focal thickening of the intimal layer, so called atherosclerotic plaques. Objectives: Despite the high priority of atherosclerosis research for global health and the numerous preclinical and clinical studies conducted, currently, there is no effective pharmacological treatment that directly impacts atherosclerotic plaques. Many knowledge gaps exist in our understanding of the mechanisms of plaque formation. In this review, we discuss the role of mitochondria in different cell types involved in atherogenesis and provide information about mtDNA mutations associated with the disease. Results: Mitochondria of blood and arterial wall cells appear to be one of the important factors in disease initiation and development. Significant experimental evidence connects oxidative stress associated with mitochondrial dysfunction and vascular disease. Moreover, mitochondrial DNA (mtDNA) deletions and mutations are being considered as potential disease markers. Further study of mtDNA damage and associated dysfunction may open new perspectives for atherosclerosis treatment. Conclusion: Mitochondria can be considered as important disease-modifying factors in several chronic pathologies. Deletions and mutations of mtDNA may be used as potential disease markers. Mitochondria-targeting antioxidant therapies appear to be promising for the development of treatment of atherosclerosis and other diseases associated with oxidative stress and chronic inflammation.

scholarly journals The Role of Matrix Metalloproteinases in the Progression and Vulnerabilization of Coronary Atherosclerotic Plaques

2021 ◽  
Vol 7 (1) ◽  
pp. 9-16
Author(s):  
Diana Opincariu ◽  
Nora Rat ◽  
Imre Benedek
Keyword(s):  
Matrix Metalloproteinases ◽  
Ventricular Remodeling ◽  
Molecular Level ◽  
Vascular Diseases ◽  
Atherosclerotic Plaques ◽  
Vascular Structure ◽  
Cardiovascular Remodeling ◽  
Atherosclerotic Lesions ◽  
Vulnerable Plaques

Abstract Extracellular matrix (ECM) plays an important role in the development and progression of atherosclerotic lesions. Changes in the ECM are involved in the pathophysiology of many cardiovascular diseases, including atherosclerosis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases, also known as matrixins, with proteolytic activity in the ECM, being responsible for the process of tissue remodeling in various systemic pathologies, including cardiac and vascular diseases. MMPs play an important role in maintaining normal vascular structure, but also in secondary cardiovascular remodeling, in the formation of atherosclerotic plaques and in their vulnerabilization process. In addition to the assigned effect of MMPs in vulnerable plaques, they have a well-defined role in post-infarction ventricular remodeling and in various types of cardiomyopathies, followed by onset of congestive heart failure, with repeated hospitalizations and death. The aim of this manuscript was to provide a summary on the role of serum matrix metalloproteinases in the process of initiation, progression and complication of atherosclerotic lesions, from a molecular level to clinical applicability and risk prediction in patients with vulnerable coronary plaques.

scholarly journals Manganese in atherogenesis: detection, origin, and role

2012 ◽  
Vol 58 (3) ◽  
pp. 291-299
Author(s):  
A.P. Lozhkin ◽  
T.B. Biktagirov ◽  
O.V. Gorshkiv ◽  
E.V. Timonina ◽  
G.V. Mamin ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Fenton Reaction ◽  
Transition Metal Ions ◽  
Atherosclerotic Plaques ◽  
Oxygen Species ◽  
Degenerate Primers ◽  
Gene Encoding ◽  
Atherosclerotic Lesions ◽  
Radical Generation

The role of transition metal ions in atherogenesis is controversial; they can participate in the hydroxyl radical generation and catalyze the reactive oxygen species neutralization reaction as cofactors of antioxidant enzymes. Using EPR spectroscopy, we revealed that 70% of the samples of aorta with atherosclerotic lesions possessed superoxide dismutase activity, 100% of the samples initiated Fenton reaction and demonstrated the presence of manganese paramagnetic centers. The sodA gene encoding manganese-dependent bacterial superoxide dismutase was not found in the samples of atherosclerotic plaques by PCR using degenerate primers. The data obtained indicates the perspectives of manganese analysis as a marker element in the express diagnostics of atherosclerosis.

scholarly journals Periodontal Pathogens and Atherosclerosis: Implications of Inflammation and Oxidative Modification of LDL

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Tomoko Kurita-Ochiai ◽  
Masafumi Yamamoto
Keyword(s):  
High Fat Diet ◽  
Oxidative Modification ◽  
Periodontal Pathogen ◽  
Periodontal Pathogens ◽  
Mucosal Vaccination ◽  
Atherosclerotic Lesions ◽  
Causative Agents ◽  
Anti Inflammatory ◽  
Apoe Deficient Mouse

Inflammation is well accepted to play a crucial role in the development of atherosclerotic lesions, and recent studies have demonstrated an association between periodontal disease and cardiovascular disease.Porphyromonas gingivalisandAggregatibacter actinomycetemcomitans, causative agents of destructive chronic inflammation in the periodontium, can accelerate atheroma deposition in animal models. Emerging evidence suggests that vaccination against virulence factors of these pathogens and anti-inflammatory therapy may confer disease resistance. In this review, we focus on the role of inflammatory mechanisms and oxidative modification in the formation and activation of atherosclerotic plaques accelerated byP. gingivalisorA. actinomycetemcomitansin an ApoE-deficient mouse model and high-fat-diet-fed mice. Furthermore, we examine whether mucosal vaccination with a periodontal pathogen or the anti-inflammatory activity of catechins can reduce periodontal pathogen-accelerated atherosclerosis.

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