Protein Phosphatase 2A Activation via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome

2021 ◽  
Author(s):  
Haiyan Chu ◽  
Anastasia Sacharidou ◽  
An Nguyen ◽  
Chun Li ◽  
Ken L Chambliss ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Protein Phosphatase ◽  
In Vivo Studies ◽  
Hypertensive Disorder ◽  
Fetal Demise ◽  
Maternal Hypertension ◽  
Life Threatening ◽  
Phosphatase 2A ◽  
And Migration

Rationale: Preeclampsia (PE) is a potentially life-threatening, placenta-based hypertensive disorder during pregnancy, and the antiphospholipid syndrome (APS) frequently leads to PE. APS pregnancies are also complicated by fetal demise and intrauterine growth restriction (IUGR). Objective: Here we determined how the circulating antiphospholipid antibodies (aPL) characteristic of APS alter placental trophoblast function to cause PE and also endanger the fetus. Methods and Results: Experiments were performed in mice, in cultured human trophoblasts, and in human placenta samples. Effects of aPL and IgG from healthy subjects were compared. Based on prior findings in culture, in vivo studies were done in mice deficient in apolipoprotein E receptor 2 (ApoER2) in trophoblasts. Endpoints in tissues and cells were determined by enzymatic assay, Q-PCR, ELISA or immunoblotting. Whereas in wild-type mice aPL caused maternal hypertension and proteinuria, fetal demise and IUGR, mice lacking trophoblast ApoER2 were protected. In culture aPL attenuated trophoblast proliferation and migration via an ApoER2-related protein complex comprised of the protein phosphatase PP2A, Dab2, and JIP4. Via trophoblast ApoER2 in mice and in culture, aPL stimulated PP2A activity, leading to MMP14 and HIF1alpha upregulation and increased soluble endoglin (sEng) production. HIF1alpha and sEng upregulation was related to PP2A desphosphorylation of PHD2. In mice PP2A inhibition prevented aPL-induced maternal hypertension and proteinuria, and fetal demise and IUGR. Placentas from APS patients displayed PP2A hyperactivation, PHD2 dephosphorylation and HIF1α upregulation, and these findings were generalizable to placentas of women with PE from causes other from APS. Conclusions: In APS pregnancies trophoblasts are the critical cell target of aPL, and via ApoER2-dependent PP2A activation, aPL cause PE through MMP14 upregulation and PHD2 dephosphorylation leading to HIF1 and sEng upregulation. Moreover, parallel processes may be operative in PE in non-APS patients. Interventions targeting PP2A may provide novel means to combat APS-related PE and PE unrelated to APS.

scholarly journals The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo.

1994 ◽  
Vol 269 (23) ◽  
pp. 16311-16317 ◽  
Author(s):  
B. Favre ◽  
S. Zolnierowicz ◽  
P. Turowski ◽  
B.A. Hemmings
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Catalytic Subunit ◽  
Phosphatase 2A

scholarly journals A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jie Zheng ◽  
Na Tian ◽  
Fei Liu ◽  
Yidian Zhang ◽  
Jingfen Su ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Phosphatase ◽  
High Efficiency ◽  
Microtubule Assembly ◽  
Hyperphosphorylated Tau ◽  
Phosphatase 2A ◽  
Dependent Learning ◽  
The Brain

AbstractIntraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer’s disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.

scholarly journals Substrate stiffness-dependent exacerbation of endothelial permeability and inflammation: mechanisms and potential implications in ALI and PH (2017 Grover Conference Series)

2018 ◽  
Vol 8 (2) ◽  
pp. 204589401877304 ◽  
Author(s):  
Pratap Karki ◽  
Anna A. Birukova
Keyword(s):  
Lung Injury ◽  
Inflammatory Responses ◽  
Mechanical Strain ◽  
Endothelial Permeability ◽  
Endothelial Barrier ◽  
In Vivo Studies ◽  
Potential Implication ◽  
Vascular Stiffening ◽  
Life Threatening

The maintenance of endothelial barrier integrity is absolutely essential to prevent the vascular leak associated with pneumonia, pulmonary edema resulting from inhalation of toxins, acute elevation to high altitude, traumatic and septic lung injury, acute lung injury (ALI), and its life-threatening complication, acute respiratory distress syndrome (ARDS). In addition to the long-known edemagenic and inflammatory agonists, emerging evidences suggest that factors of endothelial cell (EC) mechanical microenvironment such as blood flow, mechanical strain of the vessel, or extracellular matrix stiffness also play an essential role in the control of endothelial permeability and inflammation. Recent studies from our group and others have demonstrated that substrate stiffening causes endothelial barrier disruption and renders EC more susceptible to agonist-induced cytoskeletal rearrangement and inflammation. Further in vivo studies have provided direct evidence that proinflammatory stimuli increase lung microvascular stiffness which in turn exacerbates endothelial permeability and inflammation and perpetuates a vicious circle of lung inflammation. Accumulating evidence suggests a key role for RhoA GTPases signaling in stiffness-dependent mechanotransduction mechanisms defining EC permeability and inflammatory responses. Vascular stiffening is also known to be a key contributor to other cardiovascular diseases such as arterial pulmonary hypertension (PH), although the precise role of stiffness in the development and progression of PH remains to be elucidated. This review summarizes the current understanding of stiffness-dependent regulation of pulmonary EC permeability and inflammation, and discusses potential implication of pulmonary vascular stiffness alterations at macro- and microscale in development and modulation of ALI and PH.

scholarly journals The Separation and 51Chromium Labeling of Human Lymphocytes With In Vivo Studies of Survival and Migration

Blood ◽  
1971 ◽  
Vol 38 (3) ◽  
pp. 360-371 ◽  
Author(s):  
PETER HERSEY
Keyword(s):  
Human Lymphocytes ◽  
Normal Subjects ◽  
The Body ◽  
In Vivo Studies ◽  
Human Beings ◽  
Lymphatic Leukemia ◽  
Circulating Lymphocytes ◽  
Relative Inability ◽  
And Migration

Abstract This study looks at the application of 51Cr labeling of lymphocytes as a method of obtaining in vivo information about the lymphocyte in human beings. Lymphocytes were separated from whole blood by methods based on isopycnic and rate zonal centrifugation techniques and the conditions for 51Cr uptake by the separated lymphocytes standardized to enable a known amount of radioactivity to be injected into the subjects under study. The uptake of the label into various sites in the body was studied by the means of surface probes linked synchronously to a digital printout device and the survival in the circulation estimated by scintillation counting of blood samples taken at various times after injection of the label. The in vivo studies of survival and migration in 10 normal subjects show an initial rapid clearance of cells from the circulation associated with an uptake of cells into spleen and liver sites, and to a lesser extent, into sites over bone marrow and the abdomen. Survival of the circulating lymphocytes after this period appears to be relatively short, with a half-life of 1.7 days. As the available evidence suggests, this short life may be due to the differential trapping of short-lived lymphocytes in the circulation at the expense of the long-lived lymphocytes. Kinetic interpretations of the data indicate an inverse exponential uptake of cells into the sites studied, and the decline over the organs appears to follow the death rate of the cells in the body as a whole. Comparisons with studies in patients having chronic lymphatic leukemia show a relative inability of leukemic lymphocytes to leave the circulation and enter some sites in the body. These preliminary studies indicate the potential of 51Cr labeling as a useful clinical research tool in the study of lymphocytes in human beings.

scholarly journals Loss of a Protein Phosphatase 2A Regulatory Subunit (Cdc55p) Elicits Improper Regulation of Swe1p Degradation

2000 ◽  
Vol 20 (21) ◽  
pp. 8143-8156 ◽  
Author(s):  
Haifeng Yang ◽  
Wei Jiang ◽  
Matthew Gentry ◽  
Richard L. Hallberg
Keyword(s):  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Cell Types ◽  
Regulatory Subunit ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Phosphatase 2A

ABSTRACT CDC55 encodes a Saccharomyces cerevisiaeprotein phosphatase 2A (PP2A) regulatory subunit.cdc55-null cells growing at low temperature exhibit a failure of cytokinesis and produce abnormally elongated buds, butcdc55-null cells producing the cyclin-dependent kinase Cdc28-Y19F, which is unable to be inhibited by Y19 phosphorylation, show a loss of the abnormal morphology. Furthermore,cdc55-null cells exhibit a hyperphosphorylation of Y19. For these reasons, we have examined in wild-type and cdc55-null cells the levels and activities of the kinase (Swe1p) and phosphatase (Mih1p) that normally regulate the extent of Cdc28 Y19 phosphorylation. We find that Mih1p levels are comparable in the two strains, and an estimate of the in vivo and in vitro phosphatase activity of this enzyme in the two cell types indicates no marked differences. By contrast, while Swe1p levels are similar in unsynchronized and S-phase-arrested wild-type and cdc55-null cells, Swe1 kinase is found at elevated levels in mitosis-arrestedcdc55-null cells. This excess Swe1p incdc55-null cells is the result of ectopic stabilization of this protein during G2 and M, thereby accounting for the accumulation of Swe1p in mitosis-arrested cells. We also present evidence indicating that, in cdc55-null cells, misregulated PP2A phosphatase activity is the cause of both the ectopic stabilization of Swe1p and the production of the morphologically abnormal phenotype.

scholarly journals 3D-bioprinted tracheal reconstruction: an overview

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Lidia Frejo ◽  
Daniel A. Grande
Keyword(s):  
In Vivo Studies ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Tracheal Reconstruction ◽  
Airway Reconstruction ◽  
Life Threatening ◽  
Scaffold Materials ◽  
Cellular Types

Abstract Congenital tracheomalacia and tracheal stenosis are commonly seen in premature infants. In adulthood, are typically related with chronic obstructive pulmonary disease, and can occur secondarily from tracheostomy, prolong intubation, trauma, infection and tumors. Both conditions are life-threatening when not managed properly. There are still some surgical limitations for certain pathologies, however tissue engineering is a promising approach to treat massive airway dysfunctions. 3D-bioprinting have contributed to current preclinical and clinical efforts in airway reconstruction. Several strategies have been used to overcome the difficulty of airway reconstruction such as scaffold materials, construct designs, cellular types, biologic components, hydrogels and animal models used in tracheal reconstruction. Nevertheless, additional long-term in vivo studies need to be performed to assess the efficacy and safety of tissue-engineered tracheal grafts in terms of mechanical properties, behavior and, the possibility of further stenosis development.

Systemic α1A-adrenoceptor antagonist inhibits neointimal growth after balloon injury of rat carotid artery

2003 ◽  
Vol 284 (1) ◽  
pp. H385-H392 ◽  
Author(s):  
John C. Teeters ◽  
Cauveh Erami ◽  
Hua Zhang ◽  
James E. Faber
Keyword(s):  
Vascular Disease ◽  
In Vivo Studies ◽  
The Novel ◽  
Balloon Injury ◽  
Systemic Hemodynamic ◽  
Adrenoceptor Antagonist ◽  
And Migration ◽  
Wall Injury

Previous in vitro and in vivo studies have shown that norepinephrine, acting through α1A-adrenoceptors, stimulates hypertrophy, proliferation, and migration of vascular smooth muscle cells and adventitial fibroblasts and may contribute to neointimal growth, lumen loss, and inward remodeling caused by iatrogenic wall injury and vascular disease. Our present aim was to determine whether intravenous administration of the α1A-adrenoceptor antagonist KMD-3213, at dosages without systemic hemodynamic effects, inhibits wall growth after injury. Inhibition of α1A-adrenoceptors with 12.8 and 32 μg/kg KMD-3213 had no effect on arterial pressure or renal and hindquarter resistances in anesthetized rats. A second group then received carotid balloon injury and continuous intravenous KMD-3213 at 4 and 10 μg · kg−1 · h−1for 2 wk. Mean, systolic, and diastolic arterial pressures and heart rate of conscious unrestrained rats were unaffected. KMD-3213 reduced neointima growth by ∼30 and 46% at the two doses ( P< 0.01). These data support the novel hypothesis that a direct α1A-adrenoceptor-dependent trophic action of catecholamines is augmented by injury and may contribute significantly to hypertrophic vascular disease.

scholarly journals A Novel Assay for Protein Phosphatase 2A (PP2A) Complexes In Vivo Reveals Differential Effects of Covalent Modifications on Different Saccharomyces cerevisiae PP2A Heterotrimers

2005 ◽  
Vol 4 (6) ◽  
pp. 1029-1040 ◽  
Author(s):  
Matthew S. Gentry ◽  
Yikun Li ◽  
Huijun Wei ◽  
Farhana F. Syed ◽  
Sameer H. Patel ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Posttranslational Modifications ◽  
Protein Phosphatase ◽  
Cellular Localization ◽  
Fluorescent Protein ◽  
Protein Phosphatase 2A ◽  
Catalytic Subunit ◽  
Phosphatase 2A ◽  
Covalent Modifications

ABSTRACT Protein phosphatase 2A (PP2A) catalytic subunit can be covalently modified at its carboxy terminus by phosphorylation or carboxymethylation. Determining the effects of these covalent modifications on the relative amounts and functions of different PP2A heterotrimers is essential to understanding how these modifications regulate PP2A-controlled cellular processes. In this study we have validated and used a novel in vivo assay for assessing PP2A heterotrimer formation in Saccharomyces cerevisiae: the measurement of heterotrimer-dependent localization of green fluorescent protein-PP2A subunits. This assay relies on the fact that the correct cellular localization of PP2A requires that it be fully assembled. Thus, reduced localization would occur as the result of the inability to assemble a stable heterotrimer. Using this assay, we determined the effects of PP2A C-subunit phosphorylation mimic mutations and reduction or loss of PP2A methylation on the formation and localization of PP2AB/Cdc55p and PP2AB ′ /Rts1p heterotrimers. Collectively, our findings demonstrate that phosphorylation and methylation of the PP2A catalytic subunit can influence its function both by regulating the total amount of specific PP2A heterotrimers within a cell and by altering the relative proportions of PP2AB/Cdc55p and PP2AB ′ /Rts1p heterotrimers up to 10-fold. Thus, these posttranslational modifications allow flexible, yet highly coordinated, regulation of PP2A-dependent signaling pathways that in turn modulate cell growth and function.

scholarly journals Iodine Promotes Tumorigenesis of Thyroid Cancer by Suppressing Mir-422a and Up-Regulating MAPK1

2017 ◽  
Vol 43 (4) ◽  
pp. 1325-1336 ◽  
Author(s):  
Junyi  Wang ◽  
Haiou Yang ◽  
Yiran Si ◽  
Dongzhi Hu ◽  
Yang Yu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Cancer Cells ◽  
Mitogen Activated Protein Kinase ◽  
In Vivo Studies ◽  
Mitogen Activated Protein ◽  
And Migration ◽  
Cell Migration And Proliferation ◽  
Thyroid Cancer Cells

Background/Aims: Iodine may trigger tumorigenesis and development of thyroid carcinoma, but the mechanisms involved remained elusive. MicroRNA (MiRNAs) are known to be involved in each stage of cancer development; however, the role of miRNAs in iodine-induced tumorigenesis of thyroid carcinoma remained unknown. In this study, we aimed at investigating miRNA related signaling pathway in thyroid cancer cells. Methods: Levels of miRNAs and mRNAs were determined using RT-qPCR and proteins were quantified by western blotting. Cell migration and proliferation were checked using Transwell assay and CCK8 assay respectively. Tumor xenografts in nude mice were established by subcutaneous injection of cancer cells. Results: Mitogen activated protein kinase 1 (MAPK1) was significantly up-regulated, while miR-422a was down-regulated in thyroid cancer cells cultured with high iodine; miR-422a directly bound to the 3’UTR of MAPK1 mRNA. Moreover, miR-422a negatively regulated MAPK1 expression, and down-regulated miR-422a promoted proliferation and migration of TPC-1 cells. In vivo studies also confirmed that iodine promoted tumor growth by suppressing miR-422a and up-regulating MAPK1. Conclusions: Our study illustrates a new pathway comprising iodine, miRNA and MAPK1, and defines a novel mechanism in thyroid cancer.

scholarly journals Protein Phosphatase 2A Stabilizes Human Securin, Whose Phosphorylated Forms Are Degraded via the SCF Ubiquitin Ligase

2006 ◽  
Vol 26 (11) ◽  
pp. 4017-4027 ◽  
Author(s):  
Ana M. Gil-Bernabé ◽  
Francisco Romero ◽  
M. Cristina Limón-Mortés ◽  
María Tortolero
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Anaphase Promoting Complex ◽  
Anaphase Onset ◽  
Chromatid Segregation ◽  
Phosphatase 2A ◽  
F Box Protein

ABSTRACT Sister chromatid segregation is triggered at the metaphase-to-anaphase transition by the activation of the protease separase. For most of the cell cycle, separase activity is kept in check by its association with the inhibitory chaperone securin. Activation of separase occurs at anaphase onset, when securin is targeted for destruction by the anaphase-promoting complex or cyclosome E3 ubiquitin protein ligase. This results in the release of the cohesins from chromosomes, which in turn allows the segregation of sister chromatids to opposite spindle poles. Here we show that human securin (hSecurin) forms a complex with enzymatically active protein phosphatase 2A (PP2A) and that it is a substrate of the phosphatase, both in vitro and in vivo. Treatment of cells with okadaic acid, a potent inhibitor of PP2A, results in various hyperphosphorylated forms of hSecurin which are extremely unstable, due to the action of the Skp1/Cul1/F-box protein complex ubiquitin ligase. We propose that PP2A regulates hSecurin levels by counteracting its phosphorylation, which promotes its degradation. Misregulation of this process may lead to the formation of tumors, in which overproduction of hSecurin is often observed.

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