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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 Liu1,*,
Kazuko Kobayashi*,
Jun-ichi Furukawa ,
Junko Inagaki*,
Nobuo Sakairi ,
Akimasa Iwado ,
Tatsuji Yasuda*,
Takao Koike**,
Dennis R. Voelker and
Eiji Matsuura2,*
* 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: 697709). 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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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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