Protein Phosphatase 2A Activation Via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome.
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ABSTRACT:
SUBMITTER: Chu H
PROVIDER: S-EPMC8448973 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
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Protein Phosphatase 2A Activation Via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome.
Chu Haiyan H Sacharidou Anastasia A Nguyen An A Li Chun C Chambliss Ken L KL Salmon Jane E JE Shen Yu-Min YM Lo Julie J Leone Gustavo W GW Herz Joachim J Hui David Y DY Marciano Denise K DK Abrahams Vikki M VM Natale Bryony V BV Montalbano Alina P AP Xiao Xue X Xu Lin L Natale David R DR Shaul Philip W PW Mineo Chieko C
Circulation research 20210818 7
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Project description:Antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or adverse pregnancy outcome in the presence of persistent laboratory evidence of antiphospholipid antibodies (aPLs). Preeclampsia complicates about 10-17% of pregnancies with APS. However, only early onset preeclampsia (<34 weeks of gestation) belongs to the clinical criteria of APS. The similarities in the pathophysiology of early onset preeclampsia and APS emphasize an association of these two syndromes. Overall, both are the result of a defective trophoblast invasion and decidual transformation at early gestation. Women with APS are at increased risk for prematurity; the reasons are mostly iatrogenic due to placental dysfunction, such as preeclampsia or FGR. Interestingly, women with APS have also an increased risk for preterm delivery, even in the absence of FGR and preeclampsia, and therefore it is not indicated but spontaneous. The basic treatment of APS in pregnancy is low-dose aspirin and low-molecular-weight heparin. Nevertheless, up to 20-30% of women develop complications at early and late gestation, despite basic treatment. Several additional treatment options have been proposed, with hydroxychloroquine (HCQ) being one of the most efficient. Additionally, nutritional interventions, such as intake of vitamin D, have shown promising beneficial effects. Curcumin, due to its antioxidant and anti-inflammatory properties, might be considered as an additional intervention as well.
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Project description:In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of β2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (apoER2)-dependent processes. How apoER2 molecularly links these events is unknown. Here, we show that, in endothelial cells, the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase 2A (PP2A). Disabled-2 (Dab2) recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently, Src homology domain-containing transforming protein 1 (SHC1) recruits the PP2A scaffolding subunit to the proline-rich apoER2 C terminus along with 2 distinct regulatory PP2A subunits that mediate inhibitory dephosphorylation of Akt and eNOS. In mice, the coupling of these processes in endothelium is demonstrated to underlie aPL-invoked thrombosis. By elucidating these intricacies in the pathogenesis of APS-related thrombosis, numerous potential new therapeutic targets have been identified.
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Project description:Impaired invasion of EVTs results in inadequate remodelling of arteries and poor placentation, leading to PE. TMBIM4 was found to promote the migration and invasion of human osteosarcoma U2-OS and breast cancer MCF7 cell lines. However, the effect of TMBIM4 on trophoblast biological behaviour and its relevance to PE pathophysiology remain unclear. In this study, we confirmed that TMBIM4 was highly expressed in cytotrophoblasts, syncytiotrophoblasts, and EVTs of the human placenta during early pregnancy. By comparing the expression levels of TMBIM4 in the placenta of women with normal-term pregnancy and PE, TMBIM4 was found to be significantly decreased in PE. Thereafter, we determined the expression of TMBIM4 in the LPS-treated first-trimester human trophoblast cell line HTR-8/SVneo (mimicking a PE-like cell model), and determined the effect of TMBIM4 on trophoblast function and its underlying mechanism. LPS treatment reduced the expression of TMBIM4 and induced NLRP3 inflammasome activity in HTR-8/SVneo cells. KO of TMBIM4 in the HTR-8/SVneo cell line impaired cell viability, migration, and invasion, which was more severe in the LPS/ATP-treated TMBIM4-KO cell line. Moreover, TMBIM4 deficiency enhanced NLRP3 inflammasome activity and promoted subsequent pyroptosis, with or without LPS/ATP treatment. The negative relationship between TMBIM4 expression and NLRP3 inflammatory activity was verified in PE placentas. Inhibiting the NLRP3 inflammasome with MCC950 in HTR-8/SVneo cells alleviated LPS/ATP-induced pyroptosis and damaged cell function in the TMBIM4-KO cell line. Overall, this study revealed a new PE-associated protein, TMBIM4, and its biological significance in trophoblast pyroptosis mediated by the NLRP3 inflammasome. TMBIM4 may serve as a potential target for the treatment of placental inflammation-associated PE.
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Project description:BackgroundAlthough heart transplantation is the definitive treatment for heart failure in eligible patients, both acute and chronic transplant rejection frequently occur. Protein phosphatase 2A (PP2A) activity is critical in maintaining tissue and organ homeostasis. In this study, we evaluated the effect of a novel class of small molecule activators of PP2A (SMAPs) on allograft rejection in a mouse heterotopic heart transplantation model.MethodsRecipient mice were administered with DT-061 (a pharmaceutically optimized SMAP) or vehicle by oral gavage beginning 1 d after transplantation. Histological and immunofluorescence analyses were performed to examine allograft rejection. Regulatory T cells (Treg) from recipient spleens were subjected to flow cytometry and RNA sequencing analysis. Finally, the effect of DT-061 on smooth muscle cells (SMCs) migration and proliferation was assessed.ResultsDT-061 treatment prolonged cardiac allograft survival. SMAPs effectively suppressed the inflammatory immune response while increasing Treg population in the allografts, findings corroborated by functional analysis of RNA sequencing data derived from Treg of treated splenic tissues. Importantly, SMAPs extended immunosuppressive agent cytotoxic T lymphocyte-associated antigen-4-Ig-induced cardiac transplantation tolerance and allograft survival. SMAPs also strongly mitigated cardiac allograft vasculopathy as evidenced by a marked reduction of neointimal hyperplasia and SMC proliferation. Finally, our in vitro studies implicate suppression of MEK/ERK pathways as a unifying mechanism for the effect of PP2A modulation in Treg and SMCs.ConclusionsPP2A activation prevents cardiac rejection and prolongs allograft survival in a murine model. Our findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation.
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Project description:Essentials (NZWxBXSB)F1 male mice develop antibodies beta2-glycoprotein I (?2GPI) and hypertension. A1-A1 is a soluble analogue of ApoE receptor 2 with a high affinity for ?2GPI/antibody complexes. A1-A1 improved blood pressure and arterial elastance in (NZWxBXSB)F1 male mice. A1-A1 had no adverse effects on the hemodynamics of healthy mice.Background Antiphospholipid syndrome (APS) is diagnosed based on the presence of antiphospholipid antibodies and clinical thrombosis or fetal loss during pregnancy. Lupus-prone (NZWxBXSB)F1 male mice are the mouse model of spontaneous APS. They develop anti-?2GPI antibodies, microinfarcts and hypertension. ApoER2 is a receptor that contributes to anti-?2GPI-dependent thrombosis in APS by down-regulating endothelial nitric oxide synthase activation. Objectives A1-A1 is a small protein constructed from two identical ligand-binding modules from ApoER2, containing the binding site for ?2GPI. We studied how treatment with A1-A1 affects the development of hypertension in (NZWxBXSB)F1 male mice. Methods We treated (NZWxBXSB)F1 male mice with A1-A1 for up to 4 weeks and examined changes in hemodynamics by left ventricular pressure-volume loop measurements. Results We observed improvements in blood pressure in the A1-A1 treated mice. A1-A1 prevented the deterioration of arterial elastance by decreasing systemic resistance and improving vessel compliance. We did not detect any adverse effects of the treatment in either male mice or in apparently healthy female (NZWxBXSB)F1 mice. Conclusions We demonstrated that A1-A1, which is a soluble analog of ApoER2 that binds pathological ?2GPI/anti-?2GPI complexes, has a positive impact on hemodynamics in lupus-prone mice with spontaneous anti-?2GPI antibodies and hypertension.
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Project description:Background: While heart transplantation is the standard treatment for heart failure, both acute and chronic transplant rejection frequently occur. Since the modulation of protein phosphatase PP2A activity is critical for tissue and organ homeostasis under physiological and pathophysiological conditions, PP2A may also affect the ability to tolerate transplanted organs. Here we demonstrate that administration of a novel class of small molecule activators of PP2A (SMAPs) prolonged cardiac allograft survival in a mouse heterotopic heart transplantation model. Mechanistically, SMAPs effectively suppressed the inflammatory immune response while increasing Treg population in the allografts, findings corroborated by functional analysis of RNAseq data derived from Tregs of treated splenic tissue. Importantly, SMAPs further prolonged CTLA4-Ig (an immunosuppressive agent utilized in organ transplantation)-induced cardiac rejection tolerance and extended allograft survival. SMAPs also strongly mitigated cardiac allograft vasculopathy as evidenced by a marked reduction of neointimal hyperplasia and smooth muscle cell proliferation. Mechanistic studies implicate SMAPs elicited suppression of MEK/ERK pathways as a unifying mechanism for the aforementioned effects in Tregs and SMCs. These findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation and add knowledge to the phosphatase driven regulation of the immune system in the context of organ transplantation.
2023-07-20 | GSE236206 | GEO
Project description:IntroductionWhile the type I interferon (IFN-I) pathway is crucial in autoimmunity, its role in antiphospholipid antibody (aPL)-positive subjects, including aPL carriers and antiphospholipid syndrome (APS) patients, is poorly understood. This study aims at characterizing IFN-I pathway activation within the spectrum of aPL-positive subsets.MethodsA total of 112 patients [29 aPL carriers, 31 primary APS (PAPS), 25 secondary APS (SAPS), 27 systemic lupus erythematosus (SLE) patients without aPL, and 44 healthy controls (HCs)] were recruited. IFI6, IFI44, IFI44L, MX1, IFI27, OAS1, and RSAD2 gene expression was evaluated in whole blood, and a composite index (IFN score) was calculated.ResultsAn overall activation of the IFN-I pathway was observed across the entire APS spectrum, with differences among genes based on the specific disease subset. The composite score revealed quantitative differences across subsets, being elevated in aPL carriers and PAPS patients compared to HCs (both p < 0.050) and increasing in SAPS (p < 0.010) and SLE patients (p < 0.001). An unsupervised cluster analysis identified three clusters, and correspondence analyses revealed differences in clusters usage across APS subsets (p < 0.001). A network analysis revealed different patterns characterizing different subsets. The associations between IFN-I pathway activation and clinical outcomes differed across APS subsets. Although no differences in gene expression were observed in systemic APS, the network analyses revealed specific gene-gene patterns, and a distinct distribution of the clusters previously identified was noted (p = 0.002).ConclusionIFN-I pathway activation is a common hallmark among aPL-positive individuals. Qualitative and quantitative differences across the APS spectrum can be identified, leading to the identification of distinct IFN-I signatures with different clinical values beyond traditional categorization.
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Project description:Antiphospholipid syndrome (APS) is an acquired thromboinflammatory disorder characterized by the presence of antiphospholipid antibodies as well as an increased frequency of venous or arterial thrombosis and/or obstetrical morbidity. The spectrum of disease varies from asymptomatic to a severe form characterized by widespread thrombosis and multiorgan failure, termed catastrophic APS (CAPS). CAPS affects only about ∼1% of APS patients, often presents as a thrombotic microangiopathy and has a fulminant course with >40% mortality, despite the best available therapy. Animal models have implicated complement in the pathophysiology of thrombosis in APS, with more recent data from human studies confirming the interaction between the coagulation and complement pathways. Activation of the complement cascade via antiphospholipid antibodies can cause cellular injury and promote coagulation via multiple mechanisms. Finally, analogous to classic complement-mediated diseases such as atypical hemolytic uremic syndrome, a subset of patients with APS may be at increased risk for development of CAPS because of the presence of germline variants in genes crucial for complement regulation. Together, these data make complement inhibition an attractive and potentially lifesaving therapy to mitigate morbidity and mortality in severe thrombotic APS and CAPS.
| S-EPMC8080439 | biostudies-literature
Project description:BackgroundThe criteria for antiphospholipid syndrome (APS) include severe preeclampsia and/or placental insufficiency leading to preterm delivery before 34 weeks of gestation, but this APS manifestation has been rarely studied. Thus, we report a series of severe preeclampsia occurred in patients with APS.MethodsWe retrospectively analysed data of women with APS (Sydney criteria) who experienced severe preeclampsia with delivery before 34 weeks' gestation between 2000 and 2017 at five French internal medicine departments and one Italian rheumatology unit.ResultsThe 40 women had a mean age of 30.5 ± 4.6 years at their first episode of preeclampsia; 21 were nulligravid (52.5%), 12 (30%) had already been diagnosed with APS, and 21 (52.5%) had a triple-positive antiphospholipid (aPL) antibody test. Preeclampsia occurred at a median gestational age of 25.5 weeks (IQR 23-29). It was associated with HELLP in 18 cases (45%), eclampsia in 6 (15%), placental abruption in 3 (7.5%), catastrophic APS in 3 (7.5%), and foetal and neonatal death in 11 and 15 cases. Overall, 14 (35%) children survived, born at a median gestational age of 31 weeks. Among other APS criteria, 16 women (40%) experienced at least one thrombosis, 17 (42.5%) an intrauterine foetal death, and 19 (47.5%) at least one episode of HELLP during follow-up (median 5 years, IQR = 2-8). None had three or more consecutive miscarriages. Notably, 12 women (30%) had systemic lupus erythematosus.ConclusionsSevere preeclampsia led to high mortality in the offspring. Almost half of these women experienced other APS features, but not three consecutive miscarriages.
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Project description:Antiphospholipid syndrome is one of the more common acquired causes of hypercoagulability. Its major presentations are thrombotic (arterial, venous, or microvascular) and pregnancy morbidity (miscarriages, late intrauterine fetal demise, and severe pre-eclampsia). Classification criteria include 3 different antiphospholipid antibodies: lupus anticoagulant, anticardiolipin, and anti-beta 2 glycoprotein I. Management includes both preventive strategies (low-dose aspirin, hydroxychloroquine) and long-term anticoagulation after thrombosis.
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