ω-carboxyl variants of 7-ketocholesteryl esters are ligands for β2-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages

Qingping Liu, Kazuko Kobayashi, Jun Ichi Furukawa, Junko Inagaki, Nobuo Sakairi, Akimasa Iwado, Tatsuji Yasuda, Takao Koike, Dennis R. Voelker, Eiji Matsuura

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Abstract

β2-Glycoprotein I (β2-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipid syndrome. We recently reported that β2-GPI specifically binds to oxidized LDL (oxLDL) and that the β2-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 β2-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 ω-carboxylated 7-ketocholesteryl esters are critical for β2-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 β2-GPI. Liposome binding to macrophages was significantly increased depending on the ligand's concentration, in the presence of β2-GPI and an anti-β2-GPI Ab. Synthesized variant, 7-ketocholesteryl-13-carboxytridecanoate (13-COOH-7KC), also showed a significant interaction with β2-GPI and a similar binding profile with macrophages. Methylation of the carboxyl function diminished all of the specific ligand interactions with β2-GPI. Thus, ω-carboxyl variants of 7-ketocholesteryl esters can mediate anti-β2-GPI Ab-dependent uptake of oxLDL by macrophages, and autoimmune atherogenesis linked to β2-GPI interaction with oxLDL.

Original languageEnglish
Pages (from-to)1486-1495
Number of pages10
JournalJournal of Lipid Research
Volume43
Issue number9
DOIs
Publication statusPublished - Sep 2002

Fingerprint

Macrophages
Glycoproteins
Esters
Ligands
Antibodies
Ions
oxidized low density lipoprotein
Laurates
Anticardiolipin Antibodies
Methylation
Antiphospholipid Syndrome
Acetone
LDL Lipoproteins
Liposomes
Autoantibodies
Atherosclerosis
Negative ions
Positive ions
Lipids
Antigens

Keywords

  • β-glycoprotein I
  • ω-oxidation
  • Antiphospholipid syndrome
  • Atherosclerosis
  • Autoantibody
  • Oxidized LDL

ASJC Scopus subject areas

  • Endocrinology

Cite this

ω-carboxyl variants of 7-ketocholesteryl esters are ligands for β2-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages. / Liu, Qingping; Kobayashi, Kazuko; Furukawa, Jun Ichi; Inagaki, Junko; Sakairi, Nobuo; Iwado, Akimasa; Yasuda, Tatsuji; Koike, Takao; Voelker, Dennis R.; Matsuura, Eiji.

In: Journal of Lipid Research, Vol. 43, No. 9, 09.2002, p. 1486-1495.

Research output: Contribution to journalArticle

Liu, Qingping ; Kobayashi, Kazuko ; Furukawa, Jun Ichi ; Inagaki, Junko ; Sakairi, Nobuo ; Iwado, Akimasa ; Yasuda, Tatsuji ; Koike, Takao ; Voelker, Dennis R. ; Matsuura, Eiji. / ω-carboxyl variants of 7-ketocholesteryl esters are ligands for β2-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages. In: Journal of Lipid Research. 2002 ; Vol. 43, No. 9. pp. 1486-1495.
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AU - Inagaki, Junko

AU - Sakairi, Nobuo

AU - Iwado, Akimasa

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AU - Matsuura, Eiji

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N2 - β2-Glycoprotein I (β2-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipid syndrome. We recently reported that β2-GPI specifically binds to oxidized LDL (oxLDL) and that the β2-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 β2-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 ω-carboxylated 7-ketocholesteryl esters are critical for β2-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 β2-GPI. Liposome binding to macrophages was significantly increased depending on the ligand's concentration, in the presence of β2-GPI and an anti-β2-GPI Ab. Synthesized variant, 7-ketocholesteryl-13-carboxytridecanoate (13-COOH-7KC), also showed a significant interaction with β2-GPI and a similar binding profile with macrophages. Methylation of the carboxyl function diminished all of the specific ligand interactions with β2-GPI. Thus, ω-carboxyl variants of 7-ketocholesteryl esters can mediate anti-β2-GPI Ab-dependent uptake of oxLDL by macrophages, and autoimmune atherogenesis linked to β2-GPI interaction with oxLDL.

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