Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and pregnancy morbidity (PM) obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL). Several mechanisms that explain the development of thrombosis and PM in APS include the association of aPL with alterations in the coagulation cascade and inflammatory events. Other mechanisms disturbing cellular homeostases, such as mitochondrial dysfunction, autophagy, and cell proliferation, have been described in other autoimmune diseases. Therefore, the objective of this study was to investigate the impact of aPL from different patient populations on endothelial cell mitochondrial function, activation of the mammalian target of rapamycin (mTOR) and autophagy pathways, and cellular growth. Using an in vitro model, human umbilical vein endothelial cells (HUVECs) were treated with polyclonal immunoglobulin G (IgG) purified from the serum of women with both PM and vascular thrombosis (PM/VT), with VT only (VT), or with PM and non-criteria aPL (seronegative-obstetric APS, SN-OAPS). We included IgG from women with PM without aPL (PM/aPL-) and healthy women with previous uncomplicated pregnancies (normal human serum, NHS) as control groups. Mitochondrial function, mTOR activation, autophagy, and cell proliferation were evaluated by Western blotting, flow cytometry, and functional assays. IgG from women with PM/VT increased HUVEC mitochondrial hyperpolarization and activation of the mTOR and autophagic pathways, while IgG from patients with VT induced endothelial autophagy and cell proliferation in the absence of elevated mTOR activity or mitochondrial dysfunction. IgG from the SN-OAPS patient group had no effect on any of these HUVEC responses. In conclusion, aPL from women with PM and vascular events induce cellular stress evidenced by mitochondrial hyperpolarization and increased activation of the mTOR and autophagic pathways which may play a role in the pathogenesis of obstetric APS.

Withdrawn: SAMD1 attenuates antiphospholipid syndrome‐induced vascular injury and pregnancy complications

“…Antiphospholipid syndrome (APS) is defined as an autoimmune multisystem disease featured by the development of arterial and venous thromboembolic events and/or pathological pregnancies, mainly recurrent abortion, under the condition of persistently positive antiphospholipid antibody (aPL). [1][2][3] APS can be primary or occur in patients with systemic lupus erythematosus (SLE) or other systemic autoimmune diseases. 4 Dysregulation of immune function in APS patients produces a variety of autoantibodies, which causes thrombocytopenia while disrupting the integrity of vascular endothelial cells, leading to thrombosis.…”

“…Antiphospholipid syndrome (APS) is defined as an autoimmune multisystem disease featured by the development of arterial and venous thromboembolic events and/or pathological pregnancies, mainly recurrent abortion, under the condition of persistently positive antiphospholipid antibody (aPL) 1–3 . APS can be primary or occur in patients with systemic lupus erythematosus (SLE) or other systemic autoimmune diseases 4 .…”

Modulation of the activation of endothelial nitric oxide synthase and nitrosative stress biomarkers by aspirin triggered lipoxins: A possible mechanism of action of aspirin in the antiphospholipid syndrome

“…In addition, non‐criteria aPL were detected using an in‐house ELISA standardized in our group based on the technique published by Kwak et al 52 . and described elsewhere 53 …”

An update on inflammation in antiphospholipid syndrome

“…Another collection of recent studies evaluated endothelial activation and dysfunction in cultured endothelial cells exposed to various serum factors from APS patients [33 ▪▪ ,34,35]. One study found that IgG isolated from patients with different disease phenotypes (primary APS, secondary APS, APS refractory to treatment, and obstetric APS) resulted in the differential expression of markers related to endothelial activation and dysfunction [33 ▪▪ ].…”

“…Another study evaluated the response of human umbilical vein endothelial cells (HUVECs) upon exposure to polyclonal IgG isolated from the serum of women with both pregnancy morbidity and vascular thrombosis [34]. HUVECs were found to have increased cellular stress, as evidenced by increased mitochondrial hyperpolarization and increased activation of the mTOR and autophagic pathways [34]. A third study showed that a complex of oxidized low-density lipoprotein/ b 2 GPI/ab 2 GPI contributes to endothelial dysfunction by inhibited autophagy via PI3K/AKT/mTOR and endothelial nitric oxide synthase-signaling pathways [35].…”