Omega-carboxyl variants of 7-ketocholesteryl esters are ligands for beta(2)-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages.
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.
Liu
Qingping
Q
Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan.
Kobayashi
Kazuko
K
Furukawa
Jun-ichi
J
Inagaki
Junko
J
Sakairi
Nobuo
N
Iwado
Akimasa
A
Yasuda
Tatsuji
T
Koike
Takao
T
Voelker
Dennis R
DR
Matsuura
Eiji
E
D000906:Antibodies / Q000276:immunology*; D002788:Cholesterol Esters / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007653:Ketocholesterols / Q000378:metabolism*; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011485:Protein Binding; D053482:beta 2-Glycoprotein I
D000906:Antibodies; D002788:Cholesterol Esters; D006023:Glycoproteins; D007653:Ketocholesterols; D008024:Ligands; D008077:Lipoproteins, LDL; D008081:Liposomes; D053482:beta 2-Glycoprotein I; C099252:oxidized low density lipoprotein; C003001:7-ketocholesterol