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.
Highlights
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and/or obstetric events together with persistent high titers of circulating antiphospholipid antibodies (Miyakis et al, 2006)
This study aimed to establish a link between endothelial cell mitochondrial dysfunction, mammalian target of rapamycin (mTOR) activation, and autophagy in the context of aPL, it was performed in a descriptive way
Our findings have shown endothelial cell mitochondrial dysfunction in association with activation of the mTOR pathway and concurrent autophagic activity in response immunoglobulin G (IgG) from patients with pregnancy morbidity (PM)/VT, while IgG from patients with VT only induced endothelial autophagy and cell proliferation in the absence of elevated mTOR activity or mitochondrial dysfunction
Summary
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by thrombosis and/or obstetric events together with persistent high titers of circulating antiphospholipid antibodies (aPL) (Miyakis et al, 2006). In addition to the aforementioned clinical diagnostics defined by the Sapporo criteria (Miyakis et al, 2006), there are other clinical presentations not included. These manifestations can be hematologic (thrombocytopenia and hemolytic anemia), cardiac (heart valve disease), cutaneous (livedo reticularis), renal (nephropathy), or neurologic (cognitive dysfunction not associated with stroke) (Ziporen et al, 1996; Asherson et al, 2003; Garcia and Erkan, 2018; Turrent-Carriles et al, 2018; Kolitz et al, 2019). The estimated frequency of aPL in thrombotic complications was reported to be 9.5% for deep vein thrombosis, 11% for myocardial infarction, and 13.5% for stroke (Andreoli et al, 2013), the latter being more associated in patients under 50 years of age (Petri, 2000). The prevalence of obstetric complications was reported to be between 6 and 50% (Andreoli et al, 2013; Alijotas-Reig et al, 2015; Cervera et al, 2015; Esteve-Valverde et al, 2016)
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