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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.

Author:
  • Alexandru Schiopu
  • Björn Frendéus
  • Bo Jansson
  • Ingrid Söderberg
  • Irena Ljungcrantz
  • Zufan Araya
  • Prediman K Shah
  • Roland Carlsson
  • Jan Nilsson
  • Gunilla Nordin Fredrikson
Publishing year: 2007
Language: English
Pages: 2313-2318
Publication/Series: Journal of the American College of Cardiology
Volume: 50
Issue: 24
Document type: Journal article
Publisher: Elsevier USA

Abstract english

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.

Keywords

  • Cardiac and Cardiovascular Systems
  • 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

Other

Published
  • Cardiovascular Research - Immunity and Atherosclerosis
  • ISSN: 0735-1097
E-mail: jan [dot] nilsson [at] med [dot] lu [dot] se

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