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

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.

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Recent advances in understanding antiphospholipid syndrome

F1000Research ◽

10.12688/f1000research.9717.1 ◽

2016 ◽

Vol 5 ◽

pp. 2908 ◽

Cited By ~ 12

Author(s):

Maria Laura Bertolaccini ◽

Giovanni Sanna

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Anticardiolipin Antibodies ◽

Coagulation Cascade ◽

Systemic Autoimmune Disease ◽

Vascular Thrombosis ◽

Clinical Criteria ◽

Pregnancy Morbidity ◽

Glycoprotein I ◽

Hughes Syndrome

Antiphospholipid syndrome (APS), also known as Hughes Syndrome, is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies. A patient with APS must meet at least one of two clinical criteria (vascular thrombosis or complications of pregnancy) and at least one of two laboratory criteria including the persistent presence of lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and/or anti-b2 glycoprotein I (anti-b2GPI) antibodies of IgG or IgM isotype at medium to high titres in patient’s plasma. However, several other autoantibodies targeting other coagulation cascade proteins (i.e. prothrombin) or their complex with phospholipids (i.e. phosphatidylserine/prothrombin complex), or to some domains of β2GPI, have been proposed to be also relevant to APS. In fact, the value of testing for new aPL specificities in the identification of APS in thrombosis and/or pregnancy morbidity patients is currently being investigated.

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Assessment of the impact of mitochondrial genotype upon drug-induced mitochondrial dysfunction in platelets derived from healthy volunteers

Archives of Toxicology ◽

10.1007/s00204-021-02988-3 ◽

2021 ◽

Author(s):

Amy L. Ball ◽

Katarzyna M. Bloch ◽

Lucille Rainbow ◽

Xuan Liu ◽

John Kenny ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Healthy Volunteers ◽

Adverse Drug Reactions ◽

Mitochondrial Function ◽

Flux Analysis ◽

Drug Reactions ◽

Drug Induced ◽

Mtdna Variation ◽

Mitochondrial Genotype ◽

The Impact

AbstractMitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions. Despite these findings, there are currently limited models to assess the effect of mtDNA variation upon susceptibility to adverse drug reactions. Platelets offer a potential personalised model of this variation, as their anucleate nature offers a source of mtDNA without interference from the nuclear genome. This study, therefore, aimed to determine the effect of mtDNA variation upon mitochondrial function and drug-induced mitochondrial dysfunction in a platelet model. The mtDNA haplogroup of 383 healthy volunteers was determined using next-generation mtDNA sequencing (Illumina MiSeq). Subsequently, 30 of these volunteers from mitochondrial haplogroups H, J, T and U were recalled to donate fresh, whole blood from which platelets were isolated. Platelet mitochondrial function was tested at basal state and upon treatment with compounds associated with both mitochondrial dysfunction and adverse drug reactions, flutamide, 2-hydroxyflutamide and tolcapone (10–250 μM) using extracellular flux analysis. This study has demonstrated that freshly-isolated platelets are a practical, primary cell model, which is amenable to the study of drug-induced mitochondrial dysfunction. Specifically, platelets from donors of haplogroup J have been found to have increased susceptibility to the inhibition of complex I-driven respiration by 2-hydroxyflutamide. At a time when individual susceptibility to adverse drug reactions is not fully understood, this study provides evidence that inter-individual variation in mitochondrial genotype could be a factor in determining sensitivity to mitochondrial toxicants associated with costly adverse drug reactions.

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Rooibos Flavonoids, Aspalathin, Isoorientin, and Orientin Ameliorate Antimycin A-Induced Mitochondrial Dysfunction by Improving Mitochondrial Bioenergetics in Cultured Skeletal Muscle Cells

Molecules ◽

10.3390/molecules26206289 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6289

Author(s):

Sinenhlanhla X. H. Mthembu ◽

Christo J. F. Muller ◽

Phiwayinkosi V. Dludla ◽

Evelyn Madoroba ◽

Abidemi P. Kappo ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

C2c12 Myotubes ◽

Antimycin A ◽

Mrna Levels ◽

Expression Of Genes ◽

Rooibos Tea ◽

The Impact ◽

Dietary Flavonoids

The current study investigated the physiological effects of flavonoids found in daily consumed rooibos tea, aspalathin, isoorientin, and orientin on improving processes involved in mitochondrial function in C2C12 myotubes. To achieve this, C2C12 myotubes were exposed to a mitochondrial channel blocker, antimycin A (6.25 µM), for 12 h to induce mitochondrial dysfunction. Thereafter, cells were treated with aspalathin, isoorientin, and orientin (10 µM) for 4 h, while metformin (1 µM) and insulin (1 µM) were used as comparators. Relevant bioassays and real-time PCR were conducted to assess the impact of treatment compounds on some markers of mitochondrial function. Our results showed that antimycin A induced alterations in the mitochondrial respiration process and mRNA levels of genes involved in energy production. In fact, aspalathin, isoorientin, and orientin reversed such effects leading to the reduced production of intracellular reactive oxygen species. These flavonoids further enhanced the expression of genes involved in mitochondrial function, such as Ucp 2, Complex 1/3, Sirt 1, Nrf 1, and Tfam. Overall, the current study showed that dietary flavonoids, aspalathin, isoorientin, and orientin, have the potential to be as effective as established pharmacological drugs such as metformin and insulin in protecting against mitochondrial dysfunction in a preclinical setting; however, such information should be confirmed in well-established in vivo disease models.

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Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.617588 ◽

2021 ◽

Vol 13 ◽

Cited By ~ 1

Author(s):

Afzal Misrani ◽

Sidra Tabassum ◽

Li Yang

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Mitochondrial Dynamics ◽

Mitochondrial Morphology ◽

Therapeutic Approaches ◽

The Impact ◽

And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

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Antiphospholipid syndrome: critical analysis of the diagnostic path

Lupus ◽

10.1177/0961203309360543 ◽

2010 ◽

Vol 19 (4) ◽

pp. 428-431 ◽

Cited By ~ 21

Author(s):

V. Pengo ◽

A. Banzato ◽

E. Bison ◽

G. Denas ◽

S. Padayattil Jose ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Critical Analysis ◽

Single Test ◽

Single Class ◽

Vascular Thrombosis ◽

Pregnancy Morbidity ◽

Risk Patients ◽

Pathogenic Antibodies ◽

Domain I

Antiphospholipid syndrome (APS) is diagnosed in the presence of vascular thrombosis or pregnancy morbidity occurring in patients with circulating antiphospholipid antibodies (lupus anticoagulant [LA] and/or IgG/IgM anticardiolipin [aCL] and/or IgG/IgM anti-β2glycoprotein I [aβ2GPI] antibodies). Each test may identify different autoantibodies; a single test makes the diagnosis possible when positive on two or more occasions at least 12 weeks apart. However, single test positivity may be unrelated to pathogenic antibodies, which are now considered to be a subclass of aβ2GPI antibodies directed against the domain I of this protein. Conversely, all three positive tests identify a single class of aβ2GPI antibodies, thus identifying high-risk patients with APS.

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Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome

Thrombosis and Haemostasis ◽

10.1160/th11-08-0554 ◽

2012 ◽

Vol 107 (03) ◽

pp. 423-429 ◽

Cited By ~ 52

Author(s):

Paul Seed ◽

Kiran Parmar ◽

Gary W. Moore ◽

Sara E. Stuart-Smith ◽

Beverley J. Hunt ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Complement Activation ◽

Antiphospholipid Antibodies ◽

High Titre ◽

Primary Antiphospholipid Syndrome ◽

Pregnancy Morbidity ◽

Activation Products ◽

Cardiolipin Antibodies ◽

Patient Groups ◽

Obstetric Aps

SummaryThe antiphospholipid syndrome (APS) is the association of thrombosis and recurrent pregnancy loss and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPL). Increased complement activation has been implicated in the pathogenesis of APS in animal models. It was our objective to evaluate complement activation in patients with aPL or primary antiphospholipid syndrome (PAPS). We measured complement activation products, fragments Bb and C3a–desArg by ELISA in 186 aPL/PAPS patients and 30 healthy controls. All patients with aPL had significantly increased levels of complement activation products. Fragment Bb levels (mean, 95% CI); (thrombotic APS 0.54 units/ml, 0.31–0.83, obstetric APS 0.60 units/ml,0.39–1.02, isolated aPL 0.48 units/ml, 0.29–0.85, overall 0.39 units/ml, 0.33–0.47) and C3a–desArg levels (mean, 95% CI): (thrombotic APS 261 ng/ml, 219–311, obstetric APS 308 ng/ml, 243–391, isolated aPL 258 ng/ml, 193–337, overall 225 ng/ml, 202–251) were significantly higher compared to controls (fragment Bb 0.06 units/ml, 0.03–0.11, C3a–desArg 69 ng/ml, 50–92). There were correlations between Fragment Bb and C3a–desArg levels in all patients with aPL. Receiver operator characteristic (ROC) analysis showed increased fragment Bb and C3a–desArg levels had strong associations with the presence of persistent lupus anticoagulant (area under ROC: Bb 0.89, and C3a–desArg 0.90), dual and triple aPL positivity (Bb 0.71–0.82, C3a–desArg 0.71–0.80) but not with high titre anti-cardiolipin antibodies (Bb 0.62, C3a–desArg 0.65), or anti β2-glycoprotein 1 antibodies (Bb 0.66, C3a–desArg 0.67). Complement activation is present in all patient groups within this large cohort of patients aPL. This suggests it may have a major role in the pathogenesis of APS and merits further study.

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Microparticles: An Alternative Explanation to the Behavior of Vascular Antiphospholipid Syndrome

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0041-1727111 ◽

2021 ◽

Author(s):

Daniel Álvarez ◽

Carolina Rúa ◽

Ángela P.J. Cadavid

Keyword(s):

Autoimmune Disease ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Alternative Explanation ◽

Murine Models ◽

Vascular Thrombosis ◽

Pregnancy Morbidity ◽

Clinical Presentations ◽

Obstetric Antiphospholipid Syndrome

AbstractAntiphospholipid syndrome is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies, along with occurrence of vascular thrombosis and pregnancy morbidity. The variety of antiphospholipid antibodies and their related mechanisms, as well as the behavior of disease in wide groups of patients, have led some authors to propose a differentiation of this syndrome into two independent entities: vascular and obstetric antiphospholipid syndrome. Thus, previous studies have discussed whether specific autoantibodies may be responsible for this differentiation or, in contrast, how the same antibodies are able to generate two different clinical presentations. This discussion is yet to be settled. The capability of serum IgG from patients with vascular thrombosis to trigger the biogenesis of endothelial cell-derived microparticles in vitro is one of the previously discussed differences between the clinical entities of antiphospholipid syndrome. These vesicles constitute a prothrombotic mechanism as they can directly lead to clot activation in murine models and recalcified human plasma. Nevertheless, other indirect mechanisms by which microparticles can spread a procoagulant phenotype could be critical to understanding their role in antiphospholipid syndrome. For this reason, questions regarding the cargo of microparticles, and the signaling pathways involved in their biogenesis, are of interest in attempting to explain the behavior of this autoimmune disease.

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AB0408 DOES THE PRESENCE IN THE SERUM OF ANTIPHOSPHOLIPID ANTIBODIES CORRELATE WITH SPECIFIC/NON SPECIFIC CAPILLAROSCOPIC ABNORMALITIES?

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4881 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1504.2-1504

Author(s):

G. Ferrari ◽

S. Paolino ◽

A. Sulli ◽

C. Pizzorni ◽

G. Pacini ◽

...

Keyword(s):

Lupus Erythematosus ◽

Antiphospholipid Antibodies ◽

Clinical Manifestations ◽

Statistical Correlation ◽

Systemic Autoimmune Disease ◽

Research Support ◽

Vascular Thrombosis ◽

Pregnancy Morbidity ◽

Significant Difference ◽

Cardiolipin Antibodies

Background:Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by specific vascular and obstetric manifestations and by antiphospholipid antibodies (aPL) positivity [1].To date, little is known regarding nailfold videocapillaroscopy (NVC) alterations in APS patients and in asymptomatic aPL-carriers, non-specific abnormalities being the most frequently reported [2,3,4].Objectives:To retrospectively analyze NVC alterations in APS patients and in asymptomatic aPL-carriers and to correlate NCV alterations with both clinical manifestations and serum aPL profile.Methods:Thirty-five aPL positive patients having received at least one NCV investigation (mean age 47 years, range 16-81, 31 female and 4 male) were retrospectively included in the study. For each patient complete medical history was collected with a particular attention to past vascular thrombosis and pregnancy morbidity. Patients were classified as affected by APS according to the updated Sapporo classification criteria [5]. Lupus anticoagulant (LAC), IgM and IgG anti-cardiolipin antibodies (ACL) and IgM and IgG anti-Beta2 Glycoprotein 1 (anti-B2GP1) were assessed in each patient according to the recommended procedures [5]. NCV parameters were analyzed in each patient, with a particular interest to hemorrhages or nailfold bed-parallel hemosiderin deposits (“comb-like”hemorrhages) presence [2,6]. Statistical analysis was performed by parametric and non-parametric tests.Results:Seventeen patients (mean age 49 years, range 16-81 years) were asymptomatic aPL-carriers and 18 (mean age 46 years, range 26-71 years) were affected by APS. Within APS patients, 16 had a history of vascular thrombosis and 2 had pregnancy morbidity; in 6 patients APS was secondary to other autoimmune rheumatologic conditions (3 to Systemic Lupus Erythematosus, 2 to vasculitides and 1 to Mixed Connective Tissue Disease).Among the total number of aPL-carriers and APS patients six patients showed a normal NVC pattern, 24 patients had non-specific NVC abmormalities and 5 patients had a “scleroderma-like” pattern. Interestingly, NCV microhemorrhages were significantly more frequent in APS patients than in asymptomatic aPL-carriers, both in score and in absolute (p=0.05 andp=0.04, respectively). Particularly, in APS patients “comb-like”hemorrhages had a statistically significant higher prevalence than isolated hemorrhages (p=0.03). Dilated capillaries score was significantly higher in APS patients than in asymptomatic aPL-carriers (p=0.01).Not any statistically significant difference was observed regarding other capillary parameters (score of giant capillaries, loss of capillaries, or anormal shpaes, i.e. angiogenesis). Not any statistical correlation was observed between NVC parameters and different aPL profile.Conclusion:The study shows that the total number of microhemorrhages and in particular the“comb-like”subtype, are significantly the most frequent specific abnormalities in APL patients when compared to asymptomatic aPL carriers. The presence of the “scleroderma like” NVC pattern may suggest a concomitant overlap syndrome. Not any correlation was found between aPL profile and other NVC parameters. Further studies need to develop a more specific APS NVC pattern for APS patients.References:[1]Tektonidou MG, et al RMD Open 2019; 5(1);[2]Cutolo M, Elsevier 2010, pp141-143;[3]Candela M, et al.1998:444-9;[4]Aslanidis S, et al. Clin Exp Rheumatol 2011, 29:307-9;[5]Miyakis S, et al. J Thromb Haemost 2006, 4:295–306;[6]Cutolo M, et al Best Pract Res Clin Rheumatol 2008, 22:1093-108Disclosure of Interests: :Giorgia Ferrari: None declared, Sabrina Paolino: None declared, Alberto Sulli Grant/research support from: Laboratori Baldacci, Carmen Pizzorni: None declared, Greta Pacini: None declared, Emanuele Gotelli: None declared, Adriano Lercara: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha

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AMPK, Mitochondrial Function, and Cardiovascular Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21144987 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4987 ◽

Cited By ~ 1

Author(s):

Shengnan Wu ◽

Ming-Hui Zou

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Cellular Response ◽

Adenosine Monophosphate ◽

Therapeutic Effects ◽

Ampk Signaling ◽

Mitochondrial Homeostasis ◽

Redox Sensor ◽

Intracellular Energy ◽

The Impact

Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function.

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Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome

Frontiers in Physiology ◽

10.3389/fphys.2021.764702 ◽

2021 ◽

Vol 12 ◽

Author(s):

Manuela Velásquez ◽

Luisa F. Peláez ◽

Mauricio Rojas ◽

Raúl Narváez-Sánchez ◽

Jesús A. Velásquez ◽

...

Keyword(s):

Adhesion Molecules ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Clinical Manifestations ◽

Endothelial Activation ◽

No Production ◽

Endothelin 1 ◽

New Therapies ◽

Pregnancy Morbidity ◽

Obstetric Aps

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by pregnancy morbidity or thrombosis and persistent antiphospholipid antibodies (aPL) that bind to the endothelium and induce endothelial activation, which is evidenced by the expression of adhesion molecules and the production of reactive oxygen species (ROS) and subsequent endothelial dysfunction marked by a decrease in the synthesis and release of nitric oxide (NO). These endothelial alterations are the key components for the development of severe pathological processes in APS. Patients with APS can be grouped according to the presence of other autoimmune diseases (secondary APS), thrombosis alone (thrombotic APS), pregnancy morbidity (obstetric APS), and refractoriness to conventional treatment regimens (refractory APS). Typically, patients with severe and refractory obstetric APS exhibit thrombosis and are classified as those having primary or secondary APS. The elucidation of the mechanisms underlying these alterations according to the different groups of patients with APS could help establish new therapies, particularly necessary for severe and refractory cases. Therefore, this study aimed to evaluate the differences in endothelial activation and dysfunction induced by aPL between patients with refractory obstetric APS and other APS clinical manifestations. Human umbilical vein endothelial cells (HUVECs) were stimulated with polyclonal immunoglobulin-G (IgG) from different groups of patients n = 21), including those with primary (VTI) and secondary thrombotic APS (VTII) and refractory primary (RI+), refractory secondary (RII+), and non-refractory primary (NR+) obstetric APS. All of them with thrombosis. The expression of adhesion molecules; the production of ROS, NO, vascular endothelial growth factor (VEGF), and endothelin-1; and the generation of microparticles were used to evaluate endothelial activation and dysfunction. VTI IgG induced the expression of adhesion molecules and the generation of microparticles and VEGF. RI+ IgG induced the expression of adhesion molecules and decreased NO production. RII+ IgG increased the production of microparticles, ROS, and endothelin-1 and reduced NO release. NR+ IgG increased the production of microparticles and endothelin-1 and decreased the production of VEGF and NO. These findings reveal differences in endothelial activation and dysfunction among groups of patients with APS, which should be considered in future studies to evaluate new therapies, especially in refractory cases.

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