Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model

Alves, José Delgado; Mason, Lesley; Ames, P. R. J.; Chen, P. P.; Rauch, Joyce; Levine, JS; Subang, Rebecca; Isenberg, David

doi:10.1093/rheumatology/keh722

Cited by 66 publications

(49 citation statements)

References 38 publications

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“…It is already known that anticardiolipin antibodies also have a role in coagulation alteration and in endothelial changes [8,9] and this can well explain our results.…”

Section: Resultssupporting

confidence: 83%

Carotid Atherosclerosis and Flow Mediated Dilatation in the Brachial Artery in Patients with Antiphospholipid Syndrome: A Case-control Study

Biasiolo¹,

Zancan²,

Manca³

et al. 2013

LSMR

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“…It is already known that anticardiolipin antibodies also have a role in coagulation alteration and in endothelial changes [8,9] and this can well explain our results.…”

Section: Resultssupporting

confidence: 83%

Carotid Atherosclerosis and Flow Mediated Dilatation in the Brachial Artery in Patients with Antiphospholipid Syndrome: A Case-control Study

Biasiolo¹,

Zancan²,

Manca³

et al. 2013

LSMR

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“…The latter effect was limited to IS4, the monoclonal IgG aCL, whereas, WB-CAL-1, the monoclonal IgG anti-b 2 GPI was devoid of such effect. This is in keeping with the inhibitory effects of IS4 on PONa in SCID mice, where no effect was seen for antib 2 GPI of either isotype (of a different source from the ones used here (Delgado Alves et al 2005)). Further studies are required to elucidate the interaction between aPL and PON.…”

Section: Discussionsupporting

confidence: 87%

Antibodies Against β₂‐Glycoprotein I Complexed With an Oxidised Lipoprotein Relate to Intima Thickening of Carotid Arteries in Primary Antiphospholipid Syndrome

Ames

Alves

Lopez

et al. 2006

Journal of Immunology Research

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To explore whether antibodies against b 2 -glycoprotein I (b 2 GPI) complexed to 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and to oxidised low-density lipoproteins (oxLDL) relate to paraoxonase activity (PONa) and/or intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). As many as 29 thrombotic patients with PAPS, 10 subjects with idiopathic antiphospholipid antibodies (aPL) without thrombosis, 17 thrombotic patients with inherited thrombophilia and 23 healthy controls were investigated. The following were measured in all participants: b 2 GPIoxLDL complexes, IgG anti-b 2 GPI-oxLig-1, IgG anti-b 2 GPI-oxLDL antibodies (ELISA), PONa, (para-nitrophenol method), IMT of common carotid (CC) artery, carotid bifurcation (B), internal carotid (IC) by high resolution sonography. b 2 GPI-oxLDL complex was highest in the control group ( p , 0.01), whereas, IgG anti-b 2 GPI-oxLig1 and IgG antib 2 GPI-oxLDL were highest in PAPS ( p , 0.0001). In healthy controls, b 2 GPI-oxLDL complexes positively correlated to IMT of the IC ( p ¼ 0.007) and negatively to PONa after correction for age ( p , 0.03). PONa inversely correlated with age ( p ¼ 0.008). In PAPS, IgG anti-b 2 GPI -oxLig-1 independently predicted PONa ( p ¼ 0.02) and IMT of B ( p ¼ 0.003), CC, ( p ¼ 0.03) and of IC ( p ¼ 0.04). In PAPS, PONa inversely correlated to the IMTof B, CC and IC ( p ¼ 0.01, 0.02 and 0.003, respectively). IgG anti-b 2 GPI-oxLig-1 may be involved in PAPS related atherogenesis via decreased PON activity.

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“…This syndrome, in addition to being associated with vascular thrombosis and recurrent miscarriages, is also associated with accelerated atherosclerosis and enhanced oxidative stress. [22][23][24] Studying the crystal structure of ␤2GPI in detail shows that the molecular configuration of the Cys288 to Cys326 disulfide bond in the C-terminal domain (domain V) has a unique configuration, with marked surface exposure of Cys326. 25,26 Such a configuration may be associated with participation in thio-disulfide exchange reactions with oxidoreductases.…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring free thiols within β2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress–induced cell injury

Ioannou

Zhang

Passam

et al. 2010

Blood

109

113

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␤2-Glycoprotein I (␤2GPI) is an evolutionary conserved, abundant circulating protein. Although its function remains uncertain, accumulated evidence points toward interactions with endothelial cells and components of the coagulation system, suggesting a regulatory role in vascular biology. Our group has shown that thioredoxin 1 (TRX-1) generates free thiols in ␤2GPI, a process that may have a regulatory role in platelet adhesion. This report extends these studies and shows for the first time evidence of ␤2GPI with free thiols in vivo in both multiple human and murine serum samples. To explore how the vascular surface may modulate the redox status of ␤2GPI, unstimulated human endothelial cells and EAhy926 cells are shown to be capable of amplifying the effect of free thiol generation within ␤2GPI. Multiple oxidoreductase enzymes, such as endoplasmic reticulum protein 46 (ERp 46) and TRX-1 reductase, in addition to protein disulfide isomerase are secreted on the surface of endothelial cells. Furthermore, one or more of these generated free thiols within ␤2GPI are also shown to be nitrosylated. Finally, the functional significance of these findings is explored, by showing that free thiol-containing ␤2GPI has a powerful effect in protecting endothelial cells and EAhy926 cells from oxidative stress-induced cell death. IntroductionThioredoxin 1 (TRX-1) is a ubiquitous, 12-kDa oxidoreductase enzyme whose multiple intracellular functions include reducing protein disulfides, scavenging oxygen free radicals, and redox regulation of signaling pathways involved in cell growth, apoptosis, and inflammation. 1 TRX-1 requires nitrosylation of the unpaired cysteine (Cys69) thiol to mediate key intracellular functions. 2 S-nitrosylation of thiols has been implicated as being important in several multisystemic physiologic and pathologic processes pertaining to hemostasis and vascular disease. 3 In addition to being a key intracellular molecule, TRX-1 is an enzyme also found in circulating plasma. It is released from cells in response to oxidative stress 4,5 and is found at higher levels in the circulation in a variety of acute and chronic inflammatory or metabolic conditions associated with an increase in systemic oxidative stress load. [6][7][8] Studies have shown that exogenous administration of TRX-1 exerts a protective role in animal models of high oxidative stress such as smoking and rheumatoid arthritis, 9,10 both of which represent risk factors for cardiovascular morbidity in humans. 11 Oxidative stress is known to be associated with vascular pathology in terms of promoting atherosclerotic plaque development, rupture and atherothrombosis. 12 However, the extracellular mechanism through which elevated TRX-1 may mediate a protective effect against oxidative stress-induced vascular injury has not been fully delineated.␤ 2 -Glycoprotein I (␤2GPI) is an evolutionary conserved 50-kDa plasma protein. The function of ␤2GPI remains uncertain, although it is thought to play a role in apoptotic cell clearance and coagulation through m...

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Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model

Abstract: aCL antibodies are associated with the decreased PON activity and reduced NO that may occur in the preclinical phase of APS.

Cited by 66 publications

References 38 publications

Carotid Atherosclerosis and Flow Mediated Dilatation in the Brachial Artery in Patients with Antiphospholipid Syndrome: A Case-control Study

Carotid Atherosclerosis and Flow Mediated Dilatation in the Brachial Artery in Patients with Antiphospholipid Syndrome: A Case-control Study

Antibodies Against β₂‐Glycoprotein I Complexed With an Oxidised Lipoprotein Relate to Intima Thickening of Carotid Arteries in Primary Antiphospholipid Syndrome

Naturally occurring free thiols within β2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress–induced cell injury

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Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model

Abstract: aCL antibodies are associated with the decreased PON activity and reduced NO that may occur in the preclinical phase of APS.

Cited by 66 publications

References 38 publications

Carotid Atherosclerosis and Flow Mediated Dilatation in the Brachial Artery in Patients with Antiphospholipid Syndrome: A Case-control Study

Carotid Atherosclerosis and Flow Mediated Dilatation in the Brachial Artery in Patients with Antiphospholipid Syndrome: A Case-control Study

Antibodies Against β2‐Glycoprotein I Complexed With an Oxidised Lipoprotein Relate to Intima Thickening of Carotid Arteries in Primary Antiphospholipid Syndrome

Naturally occurring free thiols within β2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress–induced cell injury

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Antibodies Against β₂‐Glycoprotein I Complexed With an Oxidised Lipoprotein Relate to Intima Thickening of Carotid Arteries in Primary Antiphospholipid Syndrome