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Journal of Lipid Research, Vol. 43, 1486-1495, September 2002
Copyright © 2002 by Lipid Research, Inc.

-Carboxyl variants of 7-ketocholesteryl esters are ligands for ß₂-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages

Qingping Liu^1,*, Kazuko Kobayashi^*, Jun-ichi Furukawa, Junko Inagaki^*, Nobuo Sakairi, Akimasa Iwado, Tatsuji Yasuda^*, Takao Koike^**, Dennis R. Voelker and Eiji Matsuura^2,*

^* Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
Division of Bioscience, Graduate School of Environment Earth Science, Hokkaido University, Sapporo 060-0810, Japan
Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
^** Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
Program in Cell Biology, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206

² To whom correspondence should be addressed. e-mail: eijimatu{at}md.okayama-u.ac.jp

ß₂-Glycoprotein I (ß₂-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipid syndrome. We recently reported that ß₂-GPI specifically binds to oxidized LDL (oxLDL) and that the ß₂-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 ß₂-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 -carboxylated 7-ketocholesteryl esters are critical for ß₂-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 ß₂-GPI. Liposome binding to macrophages was significantly increased depending on the ligand's concentration, in the presence of ß₂-GPI and an anti-ß₂-GPI Ab. Synthesized variant, 7-ketocholesteryl-13-carboxytridecanoate (13-COOH-7KC), also showed a significant interaction with ß₂-GPI and a similar binding profile with macrophages. Methylation of the carboxyl function diminished all of the specific ligand interactions with ß₂-GPI.

Thus, -carboxyl variants of 7-ketocholesteryl esters can mediate anti-ß₂-GPI Ab-dependent uptake of oxLDL by macrophages, and autoimmune atherogenesis linked to ß₂-GPI interaction with oxLDL.

Abbreviations: Ab, antibody; APS, antiphospholipid syndrome; ß₂-GPI, ß₂-glycoprotein I; oxLDL, oxidized LDL; PL, phospholipid; oxLig-1, 7-ketocholesteryl-9-carboxynonanoate; 13-COOH-7KC, 7-ketocholesteryl-13-carboxytridecanoate

Supplementary key words antiphospholipid syndrome • atherosclerosis • autoantibody • ß₂-glycoprotein I • oxidized LDL • -oxidation

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