Omega-carboxyl variants of 7-ketocholesteryl esters are ligands for beta(2)-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages

J Lipid Res. 2002 Sep;43(9):1486-95. doi: 10.1194/jlr.m20063-jlr200.

Abstract

beta(2)-Glycoprotein I (beta(2)-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipid syndrome. We recently reported that beta(2)-GPI specifically binds to oxidized LDL (oxLDL) and that the beta(2)-GPI's major ligand, oxLig-1 is 7-ketocholesteryl-9-carboxynonanoate (Kobayashi, K., E. Matsuura, Q. P. Liu, J. Furukawa, K. Kaihara, J. Inagaki, T. Atsumi, N. Sakairi, T. Yasuda, D. R. Voelker, and T. Koike. 2001. A specific ligand for beta(2)-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages. J. Lipid Res. 42: 697-709). In the present study, we demonstrate that omega-carboxylated 7-ketocholesteryl esters are critical for beta(2)-GPI binding. A positive ion mass spectrum of a novel ligand, designated oxLig-2, showed fragmented ions at m/z 383 and 441 in the presence of acetone, which share features of oxLig-1 and 7-ketocholesterol. In the negative ion mode, ions at m/z 627, 625, and 243 were observed. oxLig-2 was most likely 7-ketocholesteryl-12-carboxy (keto) dodecanoate. These ligands were recognized by beta(2)-GPI. Liposome binding to macrophages was significantly increased depending on the ligand's concentration, in the presence of beta(2)-GPI and an anti-beta(2)-GPI Ab. Synthesized variant, 7-ketocholesteryl-13-carboxytridecanoate (13-COOH-7KC), also showed a significant interaction with beta(2)-GPI and a similar binding profile with macrophages. Methylation of the carboxyl function diminished all of the specific ligand interactions with beta(2)-GPI. Thus, omega-carboxyl variants of 7-ketocholesteryl esters can mediate anti-beta(2)-GPI Ab-dependent uptake of oxLDL by macrophages, and autoimmune atherogenesis linked to beta(2)-GPI interaction with oxLDL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / immunology*
  • Cholesterol Esters / metabolism*
  • Chromatography, High Pressure Liquid
  • Glycoproteins / metabolism*
  • Humans
  • Ketocholesterols / metabolism*
  • Ligands
  • Lipoproteins, LDL / metabolism*
  • Liposomes / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Molecular Structure
  • Oxidation-Reduction
  • Protein Binding
  • beta 2-Glycoprotein I

Substances

  • Antibodies
  • Cholesterol Esters
  • Glycoproteins
  • Ketocholesterols
  • Ligands
  • Lipoproteins, LDL
  • Liposomes
  • beta 2-Glycoprotein I
  • oxidized low density lipoprotein
  • 7-ketocholesterol