Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis

Palinski, Wulf; Witztum, Joseph L.

doi:10.1046/j.1365-2796.2000.00656.x

Cited by 195 publications

(139 citation statements)

References 80 publications

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“…2 Autoantibodies against several such MDA-modified apoB-100 peptides have been found in humans. 11 The present studies show that human IgG1 generated against one of these MDA peptide sequences reduces atherosclerosis in apoE Ϫ/Ϫ mice and that this is associated with reduced accumulation of the corresponding oxLDL-associated epitope and of macrophages in atherosclerotic plaques.…”

Section: Discussionmentioning

confidence: 99%

“…The oxidation of aggregating LDL in the extracellular matrix of the artery wall leads to the formation of highly reactive lipid peroxides and aldehydes. 2,3 The LDL protein apolipoprotein B-100 (apoB-100) is degraded, and aldehydes bind to free amino groups on the peptide fragments. This is associated with activation of an inflammatory response, including endothelial expression of adhesion molecules and infiltration of monocytes/macrophages and T cells.…”

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confidence: 99%

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Recombinant Human Antibodies Against Aldehyde-Modified Apolipoprotein B-100 Peptide Sequences Inhibit Atherosclerosis

et al. 2004

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Background-Accumulation and oxidation of LDL are believed to be important initiating factors in atherosclerosis.Oxidized LDL is recognized by the immune system, and animal studies have suggested that these immune responses have a protective effect against atherosclerosis. Aldehyde-modified peptide sequences in apolipoprotein B-100 (apoB-100) are major targets for these immune responses. Methods and Results-Human IgG1 antibodies against 2 malondialdehyde (MDA)-modified apoB-100 peptide sequences were produced through screening of a single-chain antibody-fragment library and subsequent cloning into a pcDNA3 vector. Three weekly doses of these antibodies were injected into male apoE Ϫ/Ϫ mice. Phosphate-buffered saline and human IgG1 antibodies against fluorescein isothiocyanate were used as controls. One of the IgG1 antibodies significantly and dose-dependently reduced the extent of atherosclerosis as well as the plaque content of oxidized LDL epitopes and macrophages. In cell culture studies, human monocytes were incubated with native LDL or oxidized LDL, in the presence of antibodies. The same antibody induced an increase in monocyte binding and uptake of oxidized LDL. Conclusions-These findings suggest that antibodies are important mediators of atheroprotective immune responses directed to oxidized LDL. Thus, passive immunization against MDA-modified apoB-100 peptide sequences may represent a novel therapeutic approach for prevention and treatment of cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Recombinant Human Antibodies Against Aldehyde-Modified Apolipoprotein B-100 Peptide Sequences Inhibit Atherosclerosis

et al. 2004

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“…4 During oxidation of LDL, reactive aldehydes such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) are formed, which modify amino groups in arginine, lysine or histidine residues in apolipoprotein B100, the protein component of LDL. 5 However, the possibility that these reactive aldehydes could leak out of the LDL-particle and modify surrounding extracellular matrix proteins has been largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Increased aldehyde-modification of collagen type IV in symptomatic plaques – A possible cause of endothelial dysfunction

et al. 2015

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Increased aldehyde-modification of collagen type IV in symptomatic plaques -A possible cause of endothelial dysfunction.Dunér, Pontus; Goncalves, Isabel; Grufman, Helena; Edsfeldt, Andreas; To, Fong; Nitulescu, Mihaela; Nilsson, Jan; Bengtsson, Eva Link to publication Citation for published version (APA): Dunér, P., Goncalves, I., Grufman, H., Edsfeldt, A., To, F., Nitulescu, M., ... Bengtsson, E. (2015). Increased aldehyde-modification of collagen type IV in symptomatic plaques -A possible cause of endothelial dysfunction. Atherosclerosis, 240(1), 26-32. DOI: 10.101626-32. DOI: 10. /j.atherosclerosis.2015 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Abstract ObjectiveSubendothelial LDL-adhesion and its subsequent oxidation are considered as key events in the development of atherosclerotic lesions. During oxidation of LDL, reactive aldehydes such as malondialdehyde (MDA) are formed, which modify apolipoproteinB100. However, the possibility that these reactive aldehydes could leak out of the LDL-particle and modify surrounding extracellular matrix proteins has been largely unexplored. We have investigated if aldehyde-modification of collagen type IV, one of the major basement membrane components, in plaques is associated with cardiovascular events. MethodsThe amount of MDA-modified collagen type IV and native collagen type IV were determined in homogenates from 155 carotid artery lesions, removed by endarterectomy from patients with or without previous cerebrovascular events. ResultsPlaque MDA-collagen type IV, but not native collagen type IV, correlated with oxidized LDL (r=0.31, P<0.001) and lipoprotein-associated phospholipase A2 (r=0.44, P<0.001).MDA-collagen type IV was increased in lesions from symptomatic patients compared to lesions from asymptomatic patients. Autoantibodies against MDA-collagen type IV in plasma correlated with the amount of MDA-collagen type IV in lesions. MDA-modification of collagen type IV decreased endothelial cell attachment. In addition, culture of endothelial cells with MDA-modified collagen type IV increased vascular cell adhesion molecule expression and reduced the anti-coagulant proteins thrombomodulin and endothelial protein C receptor. In the lesions native collagen type IV, but not MDA-collagen type IV, was positively associated with thrombomodulin. Conclusion 3The present observations imply that aldehyde-modification of collagen type IV, associated with LDL oxidation, in atherosclerotic plaques may cause endothelial d...

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“…7,8 Epitopes of apolipoprotein B (apoB) 100 generated in association with LDL oxidation have been identified as major targets for immune responses in atherosclerosis. [9][10][11] Several studies have demonstrated increased titers of antibodies recognizing oxLDL in patients with coronary, 12 cerebral 13 or peripheral artery disease, 14 suggesting that they can serve as markers of the atherosclerotic process. 13,[15][16][17] However, whether these autoimmune responses have protective or pathogenetic effects remains to be fully elucidated.…”

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confidence: 99%

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

Asciutto¹,

Dias²,

Edsfeldt³

et al. 2015

Atherosclerosis

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Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy.Asciutto, Giuseppe; Dias, Nuno; Edsfeldt, Andreas; Alm, Ragnar; Nordin Fredrikson, Gunilla; Goncalves, Isabel; Nilsson, Jan Link to publication Citation for published version (APA): Asciutto, G., Dias, N., Edsfeldt, A., Alm, R., Nordin Fredrikson, G., Goncalves, I., & Nilsson, J. (2015). Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy. Atherosclerosis, 239(2), 289-294. DOI: 10.1016289-294. DOI: 10. /j.atherosclerosis.2015 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Methods: Native (nat) and malondialdehyde (MDA)-modified apoB p210 autoantibodies (IgM-p210nat, IgG-p210nat, IgM-p210MDA and IgG-p210MDA) were analyzed by ELISA from plasma samples of 351 patients at the time they underwent CEA. The incidence of postoperative CV events was assessed using national registers.Results: A total of 52 non-fatal and 15 fatal CV events were registered during the follow-up period (35.1 ± 16.7 months). Patients who suffered from a fatal CV event had significantly lower plasma levels of IgG-p210nat and IgG-p210MDA. Kaplan-Meier curves of event-free survival showed increased CV mortality in patients with levels of IgG-p210nat and IgGp210MDA below the median (Log Rank 7.813, p .005 and 9.105, p .003 respectively). The association between low levels of p210 IgG and fatal post-operative CV events remained significant when adjusting for age, sex, total cholesterol, HDL cholesterol, smoking habits and hypertension in a Cox Proportional Hazard model (hazard ratios (HR) IgG-p210nat below median: HR 6.7 (95% C.I. 1.5-30.6, p .013) and IgG-p210MDA below median: HR 7.8 (95% C.I. 1.7-35.5, p .008).Conclusions: The present findings support the notion that autoantibodies against LDL antigens are involved in the atherosclerotic disease process and suggest that CEA patients with low levels of IgG-p210nat and IgG-p210MDA have an increased risk of post-operative CV death.

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Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis

Cited by 195 publications

References 80 publications

Recombinant Human Antibodies Against Aldehyde-Modified Apolipoprotein B-100 Peptide Sequences Inhibit Atherosclerosis

Recombinant Human Antibodies Against Aldehyde-Modified Apolipoprotein B-100 Peptide Sequences Inhibit Atherosclerosis

Increased aldehyde-modification of collagen type IV in symptomatic plaques – A possible cause of endothelial dysfunction

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

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