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Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/low-density lipoprotein receptor(-/-) mice.

Schiopu, Alexandru LU ; Frendéus, Björn; Jansson, Bo; Söderberg, Ingrid LU ; Ljungcrantz, Irena LU ; Araya, Zufan; Shah, Prediman K; Carlsson, Roland; Nilsson, Jan LU and Nordin Fredrikson, Gunilla LU (2007) In Journal of the American College of Cardiology 50(24). p.2313-2318
Abstract
OBJECTIVES: The present study tested the hypothesis that treatment with human recombinant immunoglobulin G1 (IgG1) antibodies against a specific oxidized low-density lipoprotein (oxLDL) epitope will induce regression of existing atherosclerotic lesions in LDL receptor-deficient mice expressing apolipoprotein B-100 (apoB-100) (Apobec-1(-/-)/LDLR(-/-)). BACKGROUND: Oxidized LDL plays an essential role in the pathogenesis of atherosclerosis. We previously showed that an antibody against oxLDL reduces progression of atherosclerosis in mice. METHODS: Apobec-1(-/-)/LDLR(-/-) mice were fed a high-fat diet until they were 24 weeks and were subsequently transferred to chow. Starting at 25 weeks, mice were given 3 weekly injections of either of 2... (More)
OBJECTIVES: The present study tested the hypothesis that treatment with human recombinant immunoglobulin G1 (IgG1) antibodies against a specific oxidized low-density lipoprotein (oxLDL) epitope will induce regression of existing atherosclerotic lesions in LDL receptor-deficient mice expressing apolipoprotein B-100 (apoB-100) (Apobec-1(-/-)/LDLR(-/-)). BACKGROUND: Oxidized LDL plays an essential role in the pathogenesis of atherosclerosis. We previously showed that an antibody against oxLDL reduces progression of atherosclerosis in mice. METHODS: Apobec-1(-/-)/LDLR(-/-) mice were fed a high-fat diet until they were 24 weeks and were subsequently transferred to chow. Starting at 25 weeks, mice were given 3 weekly injections of either of 2 recombinant human IgG1 antibodies (IEI-E3 or 2D03) against a malondialdehyde-modified apoB-100 peptide sequence. RESULTS: At 25 weeks, atherosclerotic lesions covered 10.3 +/- 3.7% of the descending aorta. Transfer to chow diet resulted in a modest regression of atherosclerosis over a 5-week period (8.28 +/- 4.36%; p = NS). Antibody treatment induced additional regression of atherosclerosis by 50% (2D03; p = 0.001) and 36% (IEI-E3; p = 0.004) compared with control IgG1. The 2D03 treatment also reduced plaque inflammation, enhanced plaque expression of the adenosine triphosphate-binding cassette transporter A1, and inhibited expression of monocyte chemoattractant protein-1 in cultured monocytes. CONCLUSIONS: Human IgG1 against a specific oxLDL epitope can induce rapid and substantial regression of atherosclerotic lesions, possibly by stimulating lipid efflux and inhibiting macrophage recruitment. These recombinant human antibodies could represent a novel strategy for rapid regression/stabilization of atherosclerotic lesions. (Less)
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published
subject
keywords
Recombinant Proteins: therapeutic use, Oxidized LDL: physiology, Receptors, Peptide Fragments: immunology, Immunologic Factors: therapeutic use, Immunoglobulin G: therapeutic use, Cytidine Deaminase: physiology, Atherosclerosis: pathology, Atherosclerosis: metabolism, Atherosclerosis: drug therapy, ATP-Binding Cassette Transporters: metabolism, Apolipoprotein B-100: immunology
in
Journal of the American College of Cardiology
volume
50
issue
24
pages
2313 - 2318
publisher
Elsevier USA
external identifiers
  • pmid:18068040
  • wos:000251803800006
  • scopus:36649010572
ISSN
0735-1097
DOI
10.1016/j.jacc.2007.07.081
language
English
LU publication?
yes
id
84e544e2-15dd-4b14-a4a1-1b42303841af (old id 1035434)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18068040?dopt=Abstract
date added to LUP
2009-07-09 10:42:53
date last changed
2017-11-12 03:20:49
@article{84e544e2-15dd-4b14-a4a1-1b42303841af,
  abstract     = {OBJECTIVES: The present study tested the hypothesis that treatment with human recombinant immunoglobulin G1 (IgG1) antibodies against a specific oxidized low-density lipoprotein (oxLDL) epitope will induce regression of existing atherosclerotic lesions in LDL receptor-deficient mice expressing apolipoprotein B-100 (apoB-100) (Apobec-1(-/-)/LDLR(-/-)). BACKGROUND: Oxidized LDL plays an essential role in the pathogenesis of atherosclerosis. We previously showed that an antibody against oxLDL reduces progression of atherosclerosis in mice. METHODS: Apobec-1(-/-)/LDLR(-/-) mice were fed a high-fat diet until they were 24 weeks and were subsequently transferred to chow. Starting at 25 weeks, mice were given 3 weekly injections of either of 2 recombinant human IgG1 antibodies (IEI-E3 or 2D03) against a malondialdehyde-modified apoB-100 peptide sequence. RESULTS: At 25 weeks, atherosclerotic lesions covered 10.3 +/- 3.7% of the descending aorta. Transfer to chow diet resulted in a modest regression of atherosclerosis over a 5-week period (8.28 +/- 4.36%; p = NS). Antibody treatment induced additional regression of atherosclerosis by 50% (2D03; p = 0.001) and 36% (IEI-E3; p = 0.004) compared with control IgG1. The 2D03 treatment also reduced plaque inflammation, enhanced plaque expression of the adenosine triphosphate-binding cassette transporter A1, and inhibited expression of monocyte chemoattractant protein-1 in cultured monocytes. CONCLUSIONS: Human IgG1 against a specific oxLDL epitope can induce rapid and substantial regression of atherosclerotic lesions, possibly by stimulating lipid efflux and inhibiting macrophage recruitment. These recombinant human antibodies could represent a novel strategy for rapid regression/stabilization of atherosclerotic lesions.},
  author       = {Schiopu, Alexandru and Frendéus, Björn and Jansson, Bo and Söderberg, Ingrid and Ljungcrantz, Irena and Araya, Zufan and Shah, Prediman K and Carlsson, Roland and Nilsson, Jan and Nordin Fredrikson, Gunilla},
  issn         = {0735-1097},
  keyword      = {Recombinant Proteins: therapeutic use,Oxidized LDL: physiology,Receptors,Peptide Fragments: immunology,Immunologic Factors: therapeutic use,Immunoglobulin G: therapeutic use,Cytidine Deaminase: physiology,Atherosclerosis: pathology,Atherosclerosis: metabolism,Atherosclerosis: drug therapy,ATP-Binding Cassette Transporters: metabolism,Apolipoprotein B-100: immunology},
  language     = {eng},
  number       = {24},
  pages        = {2313--2318},
  publisher    = {Elsevier USA},
  series       = {Journal of the American College of Cardiology},
  title        = {Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/low-density lipoprotein receptor(-/-) mice.},
  url          = {http://dx.doi.org/10.1016/j.jacc.2007.07.081},
  volume       = {50},
  year         = {2007},
}