scholarly journals The Atherogenic Role of Circulating Modified Lipids in Atherosclerosis

2019 ◽  
Vol 20 (14) ◽  
pp. 3561 ◽  
Author(s):  
Summerhill ◽  
Grechko ◽  
Yet ◽  
Sobenin ◽  
Orekhov
Keyword(s):  
Immune Complexes ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Diagnostic Biomarkers ◽  
Modified Ldl ◽  
Atherosclerotic Lesions ◽  
Ldl Particles ◽  
Atherosclerosis Development ◽  
Accumulation Of Lipids

Lipid accumulation in the arterial wall is a crucial event in the development of atherosclerotic lesions. Circulating low-density lipoprotein (LDL) is the major source of lipids that accumulate in the atherosclerotic plaques. It was discovered that not all LDL is atherogenic. In the blood plasma of atherosclerotic patients, LDL particles are the subject of multiple enzymatic and non-enzymatic modifications that determine their atherogenicity. Desialylation is the primary and the most important atherogenic LDL modification followed by a cascade of other modifications that also increase blood atherogenicity. The enzyme trans-sialidase is responsible for the desialylation of LDL, therefore, its activity plays an important role in atherosclerosis development. Moreover, circulating modified LDL is associated with immune complexes that also have a strong atherogenic potential. Moreover, it was shown that antibodies to modified LDL are also atherogenic. The properties of modified LDL were described, and the strong evidence indicating that it is capable of inducing intracellular accumulation of lipids was presented. The accumulated evidence indicated that the molecular properties of modified LDL, including LDL-containing immune complexes can serve as the prognostic/diagnostic biomarkers and molecular targets for the development of anti-atherosclerotic drugs.

scholarly journals Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARγ signature

2019 ◽  
Author(s):  
Sara Oppi ◽  
Stefanie Nusser-Stein ◽  
Przemyslaw Blyszczuk ◽  
Xu Wang ◽  
Anne Jomard ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Myeloid Cell ◽  
Foam Cell Formation ◽  
Low Density ◽  
Enhanced Expression ◽  
Atherosclerosis Development

Abstract Aims Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. Methods and results We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques. Conclusions Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1–PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients.

scholarly journals On the pathogenesis of atherosclerosis: enzymatic transformation of human low density lipoprotein to an atherogenic moiety.

1995 ◽  
Vol 182 (6) ◽  
pp. 1959-1971 ◽  
Author(s):  
S Bhakdi ◽  
B Dorweiler ◽  
R Kirchmann ◽  
J Torzewski ◽  
E Weise ◽  
...  
Keyword(s):  
Alternative Pathway ◽  
Combined Treatment ◽  
Density Lipoprotein ◽  
Enzyme Treatment ◽  
Uniform Structure ◽  
Modified Ldl ◽  
Atherosclerotic Lesions ◽  
Ldl Particles ◽  
Ester Formation ◽  
Oxidatively Modified

Combined treatment with trypsin, cholesterol esterase, and neuraminidase transforms LDL, but not HDL or VLDL, to particles with properties akin to those of lipid extracted from atherosclerotic lesions. Single or double enzyme modifications, or treatment with phospholipase C, or simple vortexing are ineffective. Triple enzyme treatment disrupts the ordered and uniform structure of LDL particles, and gives rise to the formation of inhomogeneous lipid droplets 10-200 nm in diameter with a pronounced net negative charge, but lacking significant amounts of oxidized lipid. Enzymatically modified LDL (E-LDL), but not oxidatively modified LDL (ox-LDL), is endowed with potent complement-activating capacity. As previously found for lipid isolated from atherosclerotic lesions, complement activation occurs to completion via the alternative pathway and is independent of antibody. E-LDL is rapidly taken up by human macrophages to an extent exceeding the uptake of acetylated LDL (ac-LDL) or oxidatively modified LDL. After 16 h, cholesteryl oleate ester formation induced by E-LDL (50 micrograms/ml cholesterol) was in the range of 6-10 nmol/mg protein compared with 3-6 nmol/mg induced by an equivalent amount of acetylated LDL. At this concentration, E-LDL was essentially devoid of direct cytotoxic effects. Competition experiments indicated that uptake of E-LDL was mediated in part by ox-LDL receptor(s). Thus, approximately 90% of 125I-ox-LDL degradation was inhibited by a 2-fold excess of unlabeled E-LDL. Uptake of 125I-LDL was not inhibited by E-LDL. We hypothesize that extracellular enzymatic modification may represent an important step linking subendothelial deposition of LDL to the initiation of atherosclerosis.

Immunohistochemical Localization of Apolipoprotein B-100 (ApoB-100) and Expression of Glutathione Peroxidase (GSH-PO) in Canine Atherosclerotic Lesions

1998 ◽  
Vol 35 (3) ◽  
pp. 227-229 ◽  
Author(s):  
Y. Kagawa ◽  
E. Uchida ◽  
H. Yokota ◽  
M. Yamaguchi ◽  
H. Taniyama
Keyword(s):  
Glutathione Peroxidase ◽  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Immunohistochemical Localization ◽  
Low Density ◽  
Modified Ldl ◽  
Atherosclerotic Lesions ◽  
Foamy Cytoplasm ◽  
Tunica Intima

We used immunohistochemistry to localize canine Apolipoprotein B-100 (CApoB-100) and glutathione peroxidase (GSH-PO) in canine atherosclerotic lesions. CApoB-100 was deposited in the tunica intima and cytoplasms of infiltrating macrophages in early atherosclerotic lesions. In advanced atherosclerotic lesions, the cystic space of the lesions contained a large amount of CApoB-100 immunoreaetive material. Expression of GSH-PO was recognized in the foamy cytoplasm of macrophages and smooth muscle cells in the early and advanced atherosclerotic lesions. These results indicate that expression of GSH-PO is closely associated with the deposition of CApoB-100. In addition, they suggest that, as in human atheromas, low-density lipoprotein (LDL) is peroxidized and changed into modified LDL. Deposition of modified LDL (oxidized or acetylated) may be a critical step in the formation of canine atherosclerotic lesions.

scholarly journals Modified LDL Particles Activate Inflammatory Pathways in Monocyte-derived Macrophages: Transcriptome Analysis

2018 ◽  
Vol 24 (26) ◽  
pp. 3143-3151 ◽  
Author(s):  
Alexander N. Orekhov ◽  
Yumiko Oishi ◽  
Nikita G. Nikiforov ◽  
Andrey V. Zhelankin ◽  
Larisa Dubrovsky ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Primary Response ◽  
Secondary Response ◽  
Modified Ldl ◽  
Ldl Particles ◽  
Regulator Genes ◽  
Lipid Metabolism Genes

Background: A hallmark of atherosclerosis is its complex pathogenesis, which is dependent on altered cholesterol metabolism and inflammation. Both arms of pathogenesis involve myeloid cells. Monocytes migrating into the arterial walls interact with modified low-density lipoprotein (LDL) particles, accumulate cholesterol and convert into foam cells, which promote plaque formation and also contribute to inflammation by producing proinflammatory cytokines. A number of studies characterized transcriptomics of macrophages following interaction with modified LDL, and revealed alteration of the expression of genes responsible for inflammatory response and cholesterol metabolism. However, it is still unclear how these two processes are related to each other to contribute to atherosclerotic lesion formation. Methods: We attempted to identify the main mater regulator genes in macrophages treated with atherogenic modified LDL using a bioinformatics approach. Results: We found that most of the identified genes were involved in inflammation, and none of them was implicated in cholesterol metabolism. Among the key identified genes were interleukin (IL)-7, IL-7 receptor, IL- 15 and CXCL8. Conclusion: Our results indicate that activation of the inflammatory pathway is the primary response of the immune cells to modified LDL, while the lipid metabolism genes may be a secondary response triggered by inflammatory signalling.

scholarly journals Macrophage uptake of low-density lipoprotein bound to aggregated C-reactive protein: possible mechanism of foam-cell formation in atherosclerotic lesions

2002 ◽  
Vol 366 (1) ◽  
pp. 195-201 ◽  
Author(s):  
Tao FU ◽  
Jayme BORENSZTAJN
Keyword(s):  
Immunofluorescence Microscopy ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Dependent Manner ◽  
C Reactive Protein ◽  
Calcium Dependent ◽  
Reactive Protein ◽  
Atherosclerotic Lesions ◽  
Ldl Particles

Foam cells found in atherosclerotic lesions are believed to derive from macrophages that take up aggregated low-density lipoprotein (LDL) particles bound to the extracellular matrix of arterial walls. C-reactive protein (CRP) is an acute-phase protein found in atherosclerotic lesions, which when immobilized on a solid phase, can bind and cluster LDL particles in a calcium-dependent manner. In the present study, we examined whether CRP-bound aggregated LDL could be taken up by macrophages in culture. CRP molecules were aggregated in the presence of calcium and immobilized on the surface of polystyrene microtitre wells. Human LDL added to the wells bound to and aggregated on the immobilized CRP, also in a calcium-dependent manner. On incubation with macrophages, the immobilized CRP-bound LDL aggregates were readily taken up by the cells, as demonstrated by immunofluorescence microscopy, by the cellular accumulation of cholesterol and by the overexpression of adipophilin. Immunofluorescence microscopy and flow-cytometry analysis established that the uptake of the LDL—CRP complex was not mediated by the CRP receptor CD32. These observations with immobilized CRP and LDL, approximating the conditions that exist in the extracellular matrix of the arterial wall, thus suggest that CRP may contribute to the formation of foam cells in atherosclerotic lesions by causing the aggregation of LDL molecules that are then taken up by macrophages through a CD32-independent pathway.

scholarly journals Recognition of Oxidized Lipids by Macrophages and Its Role in Atherosclerosis Development

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 915
Author(s):  
Nataliya V. Mushenkova ◽  
Evgeny E. Bezsonov ◽  
Varvara A. Orekhova ◽  
Tatyana V. Popkova ◽  
Antonina V. Starodubova ◽  
...  
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Formation Mechanisms ◽  
Therapeutic Approaches ◽  
Macrophage Response ◽  
New Therapeutic Approaches ◽  
Metabolic Imbalance ◽  
Atherosclerosis Development

Atherosclerosis is a multifactorial chronic disease that has a prominent inflammatory component. Currently, atherosclerosis is regarded as an active autoimmune process that involves both innate and adaptive immune pathways. One of the drivers of this process is the presence of modified low-density lipoprotein (LDL). For instance, lipoprotein oxidation leads to the formation of oxidation-specific epitopes (OSE) that can be recognized by the immune cells. Macrophage response to OSEs is recognized as a key trigger for initiation and a stimulator of progression of the inflammatory process in the arteries. At the same time, the role of oxidized LDL components is not limited to pro-inflammatory stimulation, but includes immunoregulatory effects that can have protective functions. It is, therefore, important to better understand the complexity of oxidized LDL effects in atherosclerosis in order to develop new therapeutic approaches to correct the inflammatory and metabolic imbalance associated with this disorder. In this review, we discuss the process of oxidized LDL formation, mechanisms of OSE recognition by macrophages and the role of these processes in atherosclerosis.

scholarly journals Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

2021 ◽  
Vol 22 (22) ◽  
pp. 12409
Author(s):  
Jelena Vekic ◽  
Aleksandra Zeljkovic ◽  
Aleksandra Stefanovic ◽  
Rosaria Vincenza Giglio ◽  
Marcello Ciaccio ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Epidemiological Data ◽  
Beneficial Effects ◽  
Ldl Particles ◽  
Chronic Hyperglycemia

Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated.

Potential protective role of apoprotein J (clusterin) in atherogenesis: Binding to enzymatically modified low-density lipoprotein reduces fatty acid-mediated cytotoxicity

2008 ◽  
Vol 100 (07) ◽  
pp. 110-118 ◽  
Author(s):  
Cornelia A. Lux ◽  
Kerstin Paprotka ◽  
Michael Torzewski ◽  
Katrin Dersch ◽  
Claudia Koch-Brandt ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Low Density Lipoprotein ◽  
Hydrolytic Enzymes ◽  
Density Lipoprotein ◽  
Muscle Cells ◽  
Protective Role ◽  
Low Density ◽  
Modified Ldl ◽  
Atherosclerotic Lesions

SummaryFollowing entrapment in the arterial intima, low-density lipoprotein (LDL) can be modified by hydrolytic enzymes to yield a lipoprotein derivative that binds C-reactive protein, activates complement, and is rapidly taken up by monocytes/macrophages. Free fatty acids contained in enzymatically modified LDL (E-LDL) render the lipoprotein cytotoxic due to their capacity to trigger programmed cell death. Apoprotein J (ApoJ) alias clusterin is a multifunctional glycoprotein with cytoprotective and anti-inflammatory properties. It interacts with diverse substrates, is present in the intima and the media of arteries with atherosclerotic lesions and is also synthesized by smooth muscle cells during development of atherosclerosis. We report that ApoJ binds to E-LDL but not to native LDL. Binding resulted in marked reduction of cytotoxicity of E-LDL on smooth muscle cells, as revealed by determination of caspase activity, annexin binding, and cellular ATP. ApoJ was detected immunohistochemically in early atherosclerotic lesions, where it was found to colocalize with E-LDL. In atherosclerotic lesions, ApoJ may thus subserve protective functions through its capacity to inactivate C5b-9 complement complexes and by reducing the cytotoxic effects of modified LDL on cells that gain contact with the lipoprotein.

Iron-catalyzed oxidation of Trp residues in low-density lipoprotein

2011 ◽  
Vol 392 (10) ◽  
pp. 859-867 ◽  
Author(s):  
Hsin-Hung Chen ◽  
Ching-Yi Chen ◽  
Lu-Ping Chow ◽  
Chu-Huang Chen ◽  
Yuan-Teh Lee ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Experimental Studies ◽  
Density Lipoprotein ◽  
Low Density ◽  
Iron Species ◽  
Diagnostic Biomarkers ◽  
Ldl Particles ◽  
Catalyzed Oxidation

Abstract The mechanisms of oxidation of low-density lipoproteins (LDLs) are not well defined, but epidemiological and experimental studies suggest that iron-catalyzed processes may contribute to atherogenesis. The aim of this study was to test the hypothesis that iron-catalyzed oxidations of LDLs in vitro produce diagnostic biomarkers of oxidation of the apolipoprotein that could be applied to studies in vivo. LDLs were oxidized in the presence of Fe2+, EDTA, and ascorbic acid for up to 40 h. Following delipidation and trypsin digestion, the peptides were separated by HPLC, with four peaks detected at 365 nm, whereas none were observed in peptides from unoxidized LDLs. The peptides were identified by MALDI-QTOF mass spectrometry as IVQILP(W+4) EQNEQVK, IYSL(W+4)EHSTK, FEGLQE(W+4)EGK, and YH(W+4)EHTGLTLR, with (W+4) rather than the W residues of the unoxidized protein. The mass gains (+4 increase in m/z in tryptophan, W) and absorbance at 365 nm indicate kynurenines, which were trypsin-releasable peptides that are on the surface of LDL particles. All four peptides thus characterized share the sequence of WE. The preferential oxidation of W residues in WE sequences suggest contributions from the C-proximate glutamate residues in chelation of the iron species, thereby influencing site selectivities of oxidation. These kynurenine-containing peptides might serve as biomarkers of iron-mediated oxidations in vivo.

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