title: Recombinant domain V of β2-glycoprotein I inhibits the formation of atherogenic oxLDL/β2-glycoprotein I complexes.
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.
authors: 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.
authors: Jingda
authors: J
authors: Li
authors: Yan
authors: Y
authors: Chi
authors: Shuqian
authors: S
authors: Liu
authors: Le
authors: L
authors: Wang
authors: Renjun
authors: R
authors: Wang
authors: Xiaofei
authors: X
authors: Han
authors: Eiji
authors: E
authors: Matsuura
authors: Qingping
authors: Q
authors: Liu
mesh_terms: D000936:Antigen-Antibody Complex / Q000276:immunology / Q000378:metabolism*; D016736:Antiphospholipid Syndrome / Q000150:complications / Q000188:drug therapy*; D050197:Atherosclerosis; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004705:Endocytosis; D005487:Foam Cells / Q000502:physiology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000209:etiology / Q000517:prevention & control*; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D053482:beta 2-Glycoprotein I / Q000235:genetics / Q000378:metabolism*
chemical_list: C510905:7-ketocholesteryl-9-carboxynonanoate; D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D011994:Recombinant Proteins; D053482:beta 2-Glycoprotein I; C099252:oxidized low density lipoprotein