scholarly journals Apoptotic Cells with Oxidation-specific Epitopes Are Immunogenic and Proinflammatory

2004 ◽  
Vol 200 (11) ◽  
pp. 1359-1370 ◽  
Author(s):  
Mi-Kyung Chang ◽  
Christoph J. Binder ◽  
Yury I. Miller ◽  
Ganesamoorthy Subbanagounder ◽  
Gregg J. Silverman ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cell Interaction ◽  
Biologically Active ◽  
Apoptotic Cells ◽  
Proinflammatory Response ◽  
Local Inflammatory Response ◽  
Oxidatively Modified

Oxidation of low density lipoprotein (LDL) generates a variety of oxidatively modified lipids and lipid-protein adducts that are immunogenic and proinflammatory, which in turn contribute to atherogenesis. Cells undergoing apoptosis also display oxidized moieties on their surface membranes, as determined by binding of oxidation-specific monoclonal antibodies. In the present paper, we demonstrated by mass spectrometry that in comparison with viable cells, membranes of cells undergoing apoptosis contain increased levels of biologically active oxidized phospholipids (OxPLs). Indeed, immunization of mice with syngeneic apoptotic cells induced high autoantibody titers to various oxidation-specific epitopes of oxidized LDL, including OxPLs containing phosphorylcholine, whereas immunization with viable thymocytes, primary necrotic thymocytes, or phosphate-buffered saline did not. Reciprocally, these antisera specifically bound to apoptotic cells through the recognition of oxidation-specific epitopes. Moreover, splenocyte cultures from mice immunized with apoptotic cells spontaneously released significant levels of T helper cell (Th) 1 and Th2 cytokines, whereas splenocytes from controls yielded only low levels. Finally, we demonstrated that the OxPLs of apoptotic cells activated endothelial cells to induce monocyte adhesion, a proinflammatory response that was abrogated by an antibody specific to oxidized phosphatidylcholine. These results suggest that apoptotic cell death generates oxidatively modified moieties, which can induce autoimmune responses and a local inflammatory response by recruiting monocytes via monocyte–endothelial cell interaction.

scholarly journals Actin Polymerization in Macrophages in Response to Oxidized LDL and Apoptotic Cells: Role of 12/15-Lipoxygenase and Phosphoinositide 3-Kinase

2003 ◽  
Vol 14 (10) ◽  
pp. 4196-4206 ◽  
Author(s):  
Yury I. Miller ◽  
Dorothy S. Worrall ◽  
Colin D. Funk ◽  
James R. Feramisco ◽  
Joseph L. Witztum
Keyword(s):  
Cell Membrane ◽  
Actin Polymerization ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Specific Inhibitor ◽  
Density Lipoprotein ◽  
Oxidation Products ◽  
Apoptotic Cells ◽  
Lipid Oxidation Products ◽  
Phosphoinositide 3 Kinase

Formation of filamentous F-actin drives many cellular processes, including phagocytosis and cell spreading. We have recently reported that mouse macrophage 12/15-lipoxygenase (12/15-LO) activity promotes F-actin formation in filopodia during phagocytosis of apoptotic cells. Oxidized low-density lipoprotein (OxLDL) also stimulates robust F-actin formation and spreading of macrophages. However, unlike apoptotic cells, OxLDL did not cause specific translocation of 12/15-LO to the cell membrane, neither in macrophages nor in GFP-15LO–transfected COS-7 cells. Moreover, inhibition of 12/15-LO activity in macrophages by a specific inhibitor or by 12/15-LO gene disruption did not affect OxLDL-induced actin polymerization. Among LDL modifications modeling OxLDL, LDL modified by incubation with 15LO-overexpressing fibroblasts was as active in eliciting F-actin response as was OxLDL. This LDL modification is well known to produce minimally modified LDL (mmLDL), which is bioactive and carries lipid oxidation products similar to those produced by 12/15-LO catalysis. MmLDL activated phosphoinositide 3-kinase (PI3K), and PI3K inhibitors abolished mmLDL-induced macrophage spreading. We hypothesize that OxLDL and mmLDL may contribute oxidized lipids to the macrophage cell membrane and thereby mimic intracellular 12/15-LO activity, which leads to uncontrolled actin polymerization and dramatic cytoskeletal changes in macrophages.

scholarly journals Low-density lipoprotein oxidation, antioxidants, and atherosclerosis: a clinical biochemistry perspective

1996 ◽  
Vol 42 (4) ◽  
pp. 498-506 ◽  
Author(s):  
I Jialal ◽  
S Devaraj
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Direct Methods ◽  
Ldl Oxidation ◽  
Low Density ◽  
Indirect Measures ◽  
Oxidatively Modified

Abstract Cardiovascular disease is the leading cause of mortality in westernized populations. An increased concentration of plasma low-density lipoprotein (LDL) cholesterol constitutes a major risk factor for atherosclerosis. Several lines of evidence support a role for oxidatively modified LDL in atherosclerosis and for its in vivo existence. Antioxidants have been shown to decrease atherosclerotic lesion formation in animal models and decrease LDL oxidation; the evaluation of LDL oxidation in vivo is therefore very important. However, there is a paucity of methods for direct measurement of LDL oxidation. Of the direct methods currently available, the preferred ones seem to be the measurement of F2-isoprostanes, autoantibodies to epitopes on oxidized LDL, and the assessment of antioxidant status. Of the indirect measures, the most uniformly accepted procedure is examining the oxidative susceptibility of isolated LDL by monitoring conjugated diene formation.

ROCK2 associates with lectin-like oxidized LDL receptor-1 and mediates oxidized LDL-induced IL-8 production

2010 ◽  
Vol 298 (5) ◽  
pp. C1180-C1187 ◽  
Author(s):  
Mark D. Mattaliano ◽  
Joe Wooters ◽  
Heather H. Shih ◽  
Janet E. Paulsen
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Proteomics Approach ◽  
Proinflammatory Responses ◽  
Oxidatively Modified

Oxidatively modified low-density lipoprotein (OxLDL) is a contributing factor of endothelial dysfunction, an early cellular event during atherogenesis. In endothelial cells, OxLDL has been shown to stimulate proinflammatory responses, increase lipid accumulation, and induce the expression of adhesion and extracellular matrix degrading molecules. The primary receptor for OxLDL on endothelial cells has been identified as a member of the scavenger receptor family called lectin-like OxLDL receptor-1 (LOX-1). A number of studies on LOX-1 have implicated its role in multiple cardiovascular diseases including atherosclerosis. To better understand the molecular mechanisms underlying the role of LOX-1 in endothelial cells, we identified interacting proteins in an affinity-purified LOX-1 receptor complex from human aortic endothelial HAECT cells by mass spectrometry. Two molecules involved in Rho signaling pathway, ARHGEF1 and ROCK2, were identified, and their associations with LOX-1 were confirmed in reciprocal immunoprecipitation studies. Particularly, ROCK2 was found to dynamically associate with LOX-1 in the presence of OxLDL. In addition, OxLDL treatment stimulated ROCK2 catalytic activity, and ROCK2 inhibition attenuated NF-κB activation and IL-8 production resulting from OxLDL activation of LOX-1. In summary, a functional proteomics approach has enabled us to identify novel LOX-1 interactors that potentially contribute to the cellular and signaling functions of LOX-1.

scholarly journals Impaired Clearance of Apoptotic Cells Promotes Synergy between Atherogenesis and Autoimmune Disease

2004 ◽  
Vol 199 (8) ◽  
pp. 1121-1131 ◽  
Author(s):  
Tamar Aprahamian ◽  
Ian Rifkin ◽  
Ramon Bonegio ◽  
Bénédicte Hugel ◽  
Jean-Marie Freyssinet ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Apoptotic Cell ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
High Cholesterol Diet ◽  
Apoptotic Cells ◽  
Apoptotic Cell Clearance ◽  
Reduced Frequency ◽  
Cell Clearance

To clarify the link between autoimmune disease and hypercholesterolemia, we created the gld.apoE−/− mouse as a model of accelerated atherosclerosis. Atherosclerotic lesion area was significantly increased in gld.apoE−/− mice compared with apoE−/− mice. gld.apoE−/− mice also displayed increases in lymphadenopathy, splenomegaly, and autoantibodies compared with gld mice, and these effects were exacerbated by high cholesterol diet. gld.apoE−/− mice exhibited higher levels of apoptotic cells, yet a reduced frequency of engulfed apoptotic nuclei within macrophages. Infusion of lysophosphatidylcholine, a component of oxidized low density lipoprotein, markedly decreased apoptotic cell clearance in gld mice, indicating that hypercholesterolemia promotes autoimmune disease in this background. These data suggest that defects in apoptotic cell clearance promote synergy between atherosclerotic and autoimmune diseases.

Melatonin Improves Lipid Profile and Ameliorates Lipid Peroxidation in Patients with Chronic Kidney Disease.

2018 ◽  
pp. 38-45
Keyword(s):  
Lipid Peroxidation ◽  
Placebo Group ◽  
Lipid Profile ◽  
Kidney Diseases ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Before And After ◽  
Inhibit Lipid Peroxidation ◽  
Controlled Clinical Study

Dyslipidemia and oxidative modifications of lipid are frequently associated in patients with chronic kidney diseases (CKD) and considered the most important risk factors for cardiovascular events. Melatonin is a well-known potent antioxidant and has beneficial effect on lipid metabolism. the study was designed to evaluate if Melatonin could improve lipid profile and ameliorates lipid peroxidation. This single blind placebo controlled clinical study carried out on 41 patients with CKD who were randomized into two groups, control groups (n=20) those who received placebo cap and melatonin group those who received 5mg melatonin (n=21). Lipid profile [total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C)] and parameters of lipid peroxidation [oxidized LDL (oxLDL) and malondialdehyde (MDA) were measured before and after 12 weeks of the treatment. After 12 weeks of treatment, melatonin significantly increased HDL-C and decreased LDL-C compared to the initial value. The elevation in HDL-C and reduction in LDL-C were significantly different from that in placebo group. Also, both oxLDL and MDA levels significantly lowered by melatonin compared to the baseline and to the placebo group. Collectively, the results of our study showed that melatonin has advantageous effect on lipid profile and inhibit lipid peroxidation in patients with CKD.

Glycation and HMG-CoA Reductase Inhibitors: Implication in Diabetes and Associated Complications

2019 ◽  
Vol 15 (3) ◽  
pp. 213-223 ◽  
Author(s):  
Rabia Nabi ◽  
Sahir Sultan Alvi ◽  
Mohd. Saeed ◽  
Saheem Ahmad ◽  
Mohammad Salman Khan
Keyword(s):  
Oxidized Ldl ◽  
Advanced Glycation Endproducts ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Protective Role ◽  
Therapeutic Effects ◽  
Hmg Coa Reductase ◽  
Toxicological Effects ◽  
Coa Reductase

Introduction: Diabetes Mellitus (DM) acts as an absolute mediator of cardiovascular risk, prompting the prolonged occurrence, size and intricacy of atherosclerotic plaques via enhanced Advanced Glycation Endproducts (AGEs) formation. Moreover, hyperglycemia is associated with enhanced glyco-oxidized and oxidized Low-Density Lipoprotein (LDL) possessing greater atherogenicity and decreased the ability to regulate HMG-CoA reductase (HMG-R). Although aminoguanidine (AG) prevents the AGE-induced protein cross-linking due to its anti-glycation potential, it exerts several unusual pharmaco-toxicological effects thus restraining its desirable therapeutic effects. HMG-R inhibitors/statins exhibit a variety of beneficial impacts in addition to the cholesterol-lowering effects. Objective: Inhibition of AGEs interaction with receptor for AGEs (RAGE) and glyco-oxidized-LDL by HMG-R inhibitors could decrease LDL uptake by LDL-receptor (LDL-R), regulate cholesterol synthesis via HMG-R, decrease oxidative and inflammatory stress to improve the diabetes-associated complications. Conclusion: Current article appraises the pathological AGE-RAGE concerns in diabetes and its associated complications, mainly focusing on the phenomenon of both circulatory AGEs and those accumulating in tissues in diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy, discussing the potential protective role of HMG-R inhibitors against diabetic complications.

scholarly journals Oxidized LDL Modifies the Association between Proteinuria and Deterioration of Kidney Function in Proteinuric Diabetic Kidney Disease

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 504
Author(s):  
Stefanos Roumeliotis ◽  
Panagiotis I. Georgianos ◽  
Athanasios Roumeliotis ◽  
Theodoros Eleftheriadis ◽  
Aikaterini Stamou ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Function ◽  
Diabetic Kidney Disease ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Secondary Outcome ◽  
Diabetic Kidney ◽  
Egfr Decline ◽  
Over Time

Proteinuria is characterized by low accuracy for predicting onset and development of diabetic kidney disease (DKD) because it is not directly associated with molecular changes that promote DKD, but is a result of kidney damage. Oxidized low-density lipoprotein (ox-LDL) reflects oxidative stress and endothelial dysfunction, both underlying the development of proteinuria and loss of kidney function in DKD. We aimed to investigate whether ox-LDL modifies the association between proteinuria and progression of DKD in a cohort of 91 patients with proteinuric DKD and diabetic retinopathy, followed for 10 years. The primary endpoint was a combined kidney outcome of eGFR decline ≥30% or progression to end-stage kidney disease. After the end of the study, we considered the percentage change of eGFR over time as our secondary outcome. Proteinuria was associated with both outcomes, and ox-LDL amplified the magnitude of this link (p < 0.0001 for primary and p < 0.0001 for secondary outcome, respectively). After adjustment for duration of diabetes, history of cardiovascular disease and serum albumin, ox-LDL remained a significant effect modifier of the association between proteinuria and eGFR decline over time (p = 0.04). Our study shows that in proteinuric DKD, circulating ox-LDL levels amplified the magnitude of the association between proteinuria and progression of DKD.

scholarly journals Development of Capture Assays for Different Modifications of Human Low-Density Lipoprotein

2005 ◽  
Vol 12 (1) ◽  
pp. 68-75 ◽  
Author(s):  
Gabriel Virella ◽  
M. Brooks Derrick ◽  
Virginia Pate ◽  
Charlyne Chassereau ◽  
Suzanne R. Thorpe ◽  
...  
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Gas Chromatography Mass Spectrometry ◽  
Low Density ◽  
Modified Ldl ◽  
Capture Assay ◽  
Carboxymethyl Lysine

ABSTRACT Antibodies to malondialdehyde (MDA)-modified low-density lipoprotein (LDL), copper-oxidized LDL (oxLDL), N ε(carboxymethyl) lysine (CML)-modified LDL, and advanced glycosylation end product (AGE)-modified LDL were obtained by immunization of rabbits with in vitro-modified human LDL preparations. After absorption of apolipoprotein B (ApoB) antibodies, we obtained antibodies specific for each modified lipoprotein with unique patterns of reactivity. MDA-LDL antibodies reacted strongly with MDA-LDL and also with oxLDL. CML-LDL antibodies reacted strongly with CML-LDL and also AGE-LDL. oxLDL antibodies reacted with oxLDL but not with MDA-LDL, and AGE-LDL antibodies reacted with AGE-LDL but not with CML-LDL. Capture assays were set with each antiserum, and we tested their ability to capture ApoB-containing lipoproteins isolated from precipitated immune complexes (IC) and from the supernatants remaining after IC precipitation (free lipoproteins). All antibodies captured lipoproteins contained in IC more effectively than free lipoproteins. Analysis of lipoproteins in IC by gas chromatography-mass spectrometry showed that they contained MDA-LDL and CML-LDL in significantly higher concentrations than free lipoproteins. A significant correlation (r = 0.706, P < 0.019) was obtained between the MDA concentrations determined by chemical analysis and by the capture assay of lipoproteins present in IC. In conclusion, we have developed capture assays for different LDL modifications in human ApoB/E lipoprotein-rich fractions isolated from precipitated IC. This approach obviates the interference of IC in previously reported modified LDL assays and allows determination of the degree of modification of LDL with greater accuracy.

α-Tocopherol, lipids and lipoproteins in knee-joint synovial fluid and serum from patients with inflammatory joint disease

1992 ◽  
Vol 83 (6) ◽  
pp. 657-664 ◽  
Author(s):  
K. Fairburn ◽  
M. Grootveld ◽  
R. J. Ward ◽  
C. Abiuka ◽  
M. Kus ◽  
...  
Keyword(s):  
Synovial Fluid ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Levels ◽  
Biologically Active ◽  
Joint Disease ◽  
Inflammatory Joint Disease ◽  
Serum Samples ◽  
Control Serum ◽  
Inflammatory Synovial Fluid

1. We have determined the antioxidant status of synovial fluid and serum of patients with inflammatory joint disease in terms of the biologically active lipid-soluble antioxidant, α-tocopherol. Synovial fluid concentrations of α-tocopherol were significantly lower relative to those of paired serum samples (P<0.001). Serum levels of α-tocopherol in these patients did not differ significantly from those in control serum. 2. Lower concentrations of cholesterol, triacylglycerol and low-density lipoprotein were also observed in patients' synovial fluid compared with matched serum samples. However, multiple regression analysis of the data indicated that there remained a significant depletion of α-tocopherol, which was largely independent of these co-variables, in inflammatory synovial fluid. These findings are consistent with the consumption of α-tocopherol within the inflamed joint via its role in terminating the process of lipid peroxidation. 3. Nuclear magnetic resonance spectroscopic analysis of matched inflammatory synovial fluid and serum confirmed lower concentrations of triacylglycerol in synovial fluid together with evidence of a shortened mean triacylglycerol chain length. The latter metabolic difference suggests an increased utilization of triacylglycerols for energy within the inflamed joint.

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