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

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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.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No: 81270361, 30971232, 81202536, L2012435).

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Authors and Affiliations

  1. Key Laboratory of Carbohydrate and Lipid Metabolism Research, College of Life Science and Technology, Dalian University, 10-Xuefu Avenue, Dalian Economical and Technological Development Zone, Dalian, Liaoning, 116622, China

    Jingda Li, Yan Chi, Le Wang, Renjun Wang, Xiaofei Han & Qingping Liu

  2. Biomedical Engineering Department, Northwestern University, 2145 Sheridan Road, Evanston, IL, 60208‐3107, USA

    Shuqian Liu

  3. Collaborative Research Center, and Department of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Eiji Matsuura

Authors
  1. Jingda Li
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  2. Yan Chi
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  3. Shuqian Liu
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  4. Le Wang
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  5. Renjun Wang
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  6. Xiaofei Han
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  7. Eiji Matsuura
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  8. Qingping Liu
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Corresponding authors

Correspondence to Eiji Matsuura or Qingping Liu.

Additional information

Jingda Li and Yan Chi contributed equally to the work.

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Li, J., Chi, Y., Liu, S. et al. Recombinant Domain V of β2-Glycoprotein I Inhibits the Formation of Atherogenic oxLDL/β2-Glycoprotein I Complexes. J Clin Immunol 34, 669–676 (2014). https://doi.org/10.1007/s10875-014-0063-y

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  • DOI: https://doi.org/10.1007/s10875-014-0063-y

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