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

    12 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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