Involvement of beta2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages

Abstract

Anticardiolipin antibodies (aCL) in the sera of patients with antiphospholipid syndrome (APS) recognize an altered structure of beta 2-glycoprotein I (beta 2-GPI) interacting with solid-phase negatively charged phospholipids. beta 2-GPI bound to Cu2+-oxidized plasma lipoproteins, i.e. oxidized very low-density lipoprotein (oxVLDL), oxidized low-density lipoprotein (oxLDL), or oxidized high-density lipoprotein (oxHDL). beta 2-GPI inhibited in vitro uptake, i.e. cell surface binding, cellular association, and proteolytic degradation of oxLDL by murine macrophage J774A.1 cells. The binding of oxLDL to the macrophages was inhibited by the addition of polyinosinic acid (poly (I)), a competitor of the scavenger receptor, but not by another polyanionic acid, polycytidylic acid (poly (C)). Conversely, the binding of oxLDL was significantly increased by the simultaneous addition of human beta 2-GPI and monoclonal aCL derived from NZW x BXSB F1 (WB F1) mice, an animal model of APS, or anti-beta 2-GPI antibodies from BALB/c mice immunized with human beta 2-GPI. These findings indicate that beta 2-GPI may be an antiatherogenic protein and that the autoimmune response against beta 2-GPI may have a role in the development of atherosclerosis in APS.

Clinical Significance of Serum Oxidized Low-Density Lipoprotein/β₂-Glycoprotein I Complexes in Patients with Chronic Renal Diseases

“…oxLDL has been implicated in the pathogenesis of atherosclerosis [5]and previous studies suggested that immune mechanisms are involved in atherogenesis [41]. We previously demonstrated that oxLDL formed complexes with β 2 GPI, which were subsequently targeted by anti-β 2 GPI autoantibodies, considered the pathogenic autoantibodies in patients with APS [21, 22, 23, 24]. Based on these findings, we established a sandwich ELISA for detecting oxLDL/β 2 GPI complexes in serum samples.…”

“…It is now widely understood that the major autoantigen for anticardiolipin antibodies found in the sera of APS patients is β 2 -glycoprotein I (β 2 GPI) [16, 17, 18, 19, 20]. It has also been shown that β 2 GPI specifically binds to Cu 2+ -oxLDL, not to other chemically modified LDLs, and that anti-β 2 GPI autoantibodies bind to oxLDL/β 2 GPI complexes [21, 22, 23, 24]. Based on these findings, we established a novel sandwich ELISA system for the detection of serum oxLDL/β 2 GPI complexes.…”

Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q10 treatment

“…It has been shown that aPL antibodies, in particular anti-␤2GPI antibodies, can accelerate the influx of ox-LDLs into macrophages. 14 Other autoantibodies, such as anti-high-density lipoproteins (HDLs) and antiapolipoprotein A-I, also have been detected in APS. In addition, macrophages and ECs bind to ␤2GPI during the atherosclerotic process.…”

High Affinity Binding of β2-Glycoprotein I to Human Endothelial Cells Is Mediated by Annexin II

“…A role for ␤ 2 GPI as a naturally occurring anticoagulant is suggested by reports that it inhibits the prothrombinase (12) and Factor X activating complexes (13), although the physiologic importance of these effects is uncertain. ␤ 2 GPI may also promote the clearance of senescent cells (14,15) and regulate the uptake of lipoproteins by macrophages (16).…”