Recombinant Domain V of β2-Glycoprotein I Inhibits the Formation of Atherogenic oxLDL/β2-Glycoprotein I Complexes

Jingda Li, Yan Chi, Shuqian Liu, Le Wang, Renjun Wang, Xiaofei Han, Eiji Matsuura, Qingping Liu

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

β2-glycoprotein I (β2-GPI) is a plasma protein that interacts with oxidized low-density lipoproteins (oxLDL) via β2-GPI domain V to form oxLDL/β2-GPI complexes, potential autoantigens promoting atherogenesis in patients with antiphospholipid syndrome (APS). Such a interaction would expose β2-GPI domain I or/and IV, structures recognized by anti-β2-GPI autoantibodies. IgG immune complexes with oxLDL/β2-GPI complexes can interact with macrophages via Fcγ receptor, causing oxLDL/β2-GPI endocytosis and foam cell formation, contributing to atherosclerosis. Here, we use recombinant domain V to study the interaction between oxLDL and β2-GPI and hypothesized that domain V would interfere with this interaction thereby reducing oxLDL macrophage uptake and foam cell formation. The β2-GPI domain V sequence was expressed by using the Pichia pastoris expression system to obtain recombinant domain V of β2-GPI (P.rβ2-GPI DV). ELISA tests demonstrated that P.rβ2-GPI DV interacted with oxLDL via 7-ketocholesteryl-9-carboxynonanoate (oxLig-1), a negatively charged lipid moiety of oxLDL. The ω-carboxyl residue of oxLig-1 is required for the interaction. Serologic tests showed a significant increase in oxLDL and oxLDL/β2-GPI levels in patients with APS (p < 0.05 compared to controls). P.rβ2-GPI DV was able to bind oxLDL in high affinity and competitively inhibited native β2-GPI (nβ2-GPI) binding to free oxLDL as well as to oxLDL from the oxLDL/β2-GPI complexes. These observations suggest that P.rβ2-GPI DV may be used to inhibit the formation of the oxLDL/β2-GPI complexes, a potential approach for reducing foam cell development and mitigating atherogenesis in patients with APS. The present work provides a new effective strategy to prevent the progression of atherothrombotic vascular complications in APS patients.

Original languageEnglish
Pages (from-to)669-676
Number of pages8
JournalJournal of Clinical Immunology
Volume34
Issue number6
DOIs
Publication statusPublished - Aug 1 2014

Keywords

  • 7-ketocholesteryl-9-carboxynonanoate
  • Antiphospholipid syndrome
  • oxLDL/β2-GPI complexes
  • β2-GPI domain V

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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