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  1. AU="van Zuylen, Wendy J"
  2. AU="Asarnow, L D"
  3. AU="So, Ronald"
  4. AU="deSouza, Ashwin L"
  5. AU="Härtlova, Anetta"
  6. AU="Ghanem, Ahmed I"
  7. AU="Yue Lu"
  8. AU="Pincus, Laura B"
  9. AU="Ibrahim, Nashwan"
  10. AU=Bray Molly S AU=Bray Molly S
  11. AU="Bregy, Amadé"
  12. AU=Kaper J B
  13. AU="León-Ramón, Susana"
  14. AU="Simpson, Andrew"
  15. AU="Peters, Wibke"
  16. AU="Malik, Sajid Ali"
  17. AU="V, Gomathi"

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  1. Artikel ; Online: Differential Expression of PDGF Receptor-α in Human Placental Trophoblasts Leads to Different Entry Pathways by Human Cytomegalovirus Strains.

    Naing, Zin / Hamilton, Stuart T / van Zuylen, Wendy J / Scott, Gillian M / Rawlinson, William D

    Scientific reports

    2020  Band 10, Heft 1, Seite(n) 1082

    Abstract: Human cytomegalovirus (CMV) is the leading non-genetic cause of fetal malformation in developed countries. CMV placental infection is a pre-requisite for materno-fetal transmission of virus, and fetal infection. We investigated the roles of the viral ... ...

    Abstract Human cytomegalovirus (CMV) is the leading non-genetic cause of fetal malformation in developed countries. CMV placental infection is a pre-requisite for materno-fetal transmission of virus, and fetal infection. We investigated the roles of the viral pentameric complex gH/gL/pUL128-pUL131A, and cellular platelet-derived growth factor receptor-α (PDGFRα) for CMV infection in first trimester extravillous-derived (SGHPL-4) and villous-derived (HTR-8/SVneo) trophoblast cells. Infection with four CMV clinical and laboratory strains (Merlin, TB40E, Towne, AD169), and Merlin deletion mutants of UL128-, UL130-, and UL131A-genes, showed a cell type-dependent requirement of the viral pentameric complex for infection of trophoblast cells. The viral pentameric complex was essential for infection of villous trophoblasts, but non-essential for extravillous trophoblasts. Blocking of PDGFRα in extravillous trophoblasts, which naturally express PDGFRα, inhibited entry of pentameric complex-deficient CMV strains, but not the entry of pentameric positive CMV strains. Transient expression of PDGFRα in villous trophoblasts, which are naturally deficient in PDGFRα, promoted the entry of CMV strains lacking gH/gL/pUL128-pUL131A, but had no effect on entry of pentameric positive CMV strains. These results suggest PDGFRα is an important cell receptor for entry of CMV mutant strains lacking gH/gL/pUL128-pUL131A complexes in some placental cells, suggesting these entry pathways could be potential antiviral targets.
    Mesh-Begriff(e) Cell Line ; Cytomegalovirus/genetics ; Cytomegalovirus/physiology ; Cytomegalovirus Infections/genetics ; Cytomegalovirus Infections/metabolism ; Cytomegalovirus Infections/virology ; Female ; Humans ; Placenta/cytology ; Placenta/metabolism ; Placenta/virology ; Pregnancy ; Pregnancy Complications, Infectious/genetics ; Pregnancy Complications, Infectious/metabolism ; Pregnancy Complications, Infectious/virology ; Receptor, Platelet-Derived Growth Factor alpha/genetics ; Receptor, Platelet-Derived Growth Factor alpha/metabolism ; Trophoblasts/metabolism ; Trophoblasts/virology ; Viral Envelope Proteins/genetics ; Viral Envelope Proteins/metabolism ; Virus Internalization
    Chemische Substanzen Viral Envelope Proteins ; Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1)
    Sprache Englisch
    Erscheinungsdatum 2020-01-23
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-57471-3
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Detection of Ganciclovir-Resistant Cytomegalovirus in a Prospective Cohort of Kidney Transplant Recipients Receiving Subtherapeutic Valganciclovir Prophylaxis.

    Wong, Diana D / van Zuylen, Wendy J / Novos, Talia / Stocker, Sophie / Reuter, Stephanie E / Au, Jane / Foster, Charles S P / Day, Richard O / Horvath, Andrea R / Endre, Zoltan / Rawlinson, William D

    Microbiology spectrum

    2022  Band 10, Heft 3, Seite(n) e0268421

    Abstract: Cytomegalovirus infection during antiviral prophylaxis occurs in transplant recipients despite individualized regimens based on renal function. Fifty kidney transplant recipients were assessed between 2016 and 2019 for valganciclovir dosing, ganciclovir ... ...

    Abstract Cytomegalovirus infection during antiviral prophylaxis occurs in transplant recipients despite individualized regimens based on renal function. Fifty kidney transplant recipients were assessed between 2016 and 2019 for valganciclovir dosing, ganciclovir exposure, cytomegalovirus infection, and genotypic resistance markers during the first year posttransplant. Ganciclovir plasma concentrations were measured using mass spectrometry. Population pharmacokinetics was used to determine individual ganciclovir exposure and to evaluate the ability of manufacturer dosing guidelines to meet therapeutic target daily area under the curve (AUC
    Mesh-Begriff(e) Antiviral Agents/therapeutic use ; Creatinine/therapeutic use ; Cytomegalovirus/genetics ; Cytomegalovirus Infections/drug therapy ; Cytomegalovirus Infections/prevention & control ; Ganciclovir/therapeutic use ; Humans ; Kidney Transplantation/adverse effects ; Kidney Transplantation/methods ; Prospective Studies ; Transplant Recipients ; Valganciclovir/therapeutic use
    Chemische Substanzen Antiviral Agents ; Creatinine (AYI8EX34EU) ; Valganciclovir (GCU97FKN3R) ; Ganciclovir (P9G3CKZ4P5)
    Sprache Englisch
    Erscheinungsdatum 2022-06-06
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2807133-5
    ISSN 2165-0497 ; 2165-0497
    ISSN (online) 2165-0497
    ISSN 2165-0497
    DOI 10.1128/spectrum.02684-21
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Selective modulation of Wnt-binding receptor tyrosine kinase ROR2 expression by human cytomegalovirus regulates trophoblast migration.

    Huynh, Kim T / van Zuylen, Wendy J / Ford, Caroline E / Rawlinson, William D

    The Journal of general virology

    2018  Band 100, Heft 1, Seite(n) 99–104

    Abstract: Cytomegalovirus (CMV) infection during pregnancy may lead to adverse pregnancy outcomes and permanent neurological disabilities in infants infected in utero. Congenital CMV disease of the foetus and neonate results from both direct viral cytopathic ... ...

    Abstract Cytomegalovirus (CMV) infection during pregnancy may lead to adverse pregnancy outcomes and permanent neurological disabilities in infants infected in utero. Congenital CMV disease of the foetus and neonate results from both direct viral cytopathic damage and indirect effects through placental dysfunction. Infection specifically alters Wnt signalling, an essential pathway involved in trophoblast migration and placental development. We examined CMV regulation of trophoblast migration. This virus controls expression of Wnt-binding receptor tyrosine kinase ROR2, but not alternate receptor tyrosine kinases ROR1 or RYK. Ectopic expression of ROR2 reduced Wnt5a-induced trophoblast migration, whilst overexpression of ROR1 or RYK did not affect trophoblast migration. CMV infection increased ROR2 protein expression in trophoblasts, with no effect on ROR1 and RYK expression. These data further support the proposal that specific inhibition of this mechanism may be a target for therapeutic intervention to reduce placental damage and consequent foetal disease due to congenital CMV infection.
    Mesh-Begriff(e) Cell Line ; Cell Movement ; Cytomegalovirus/growth & development ; Gene Expression ; Host-Pathogen Interactions ; Humans ; Receptor Tyrosine Kinase-like Orphan Receptors/metabolism ; Trophoblasts/physiology ; Trophoblasts/virology
    Chemische Substanzen ROR2 protein, human (EC 2.7.10.1) ; Receptor Tyrosine Kinase-like Orphan Receptors (EC 2.7.10.1)
    Sprache Englisch
    Erscheinungsdatum 2018-11-15
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/jgv.0.001179
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Cytomegalovirus infection in day care centres: A systematic review and meta-analysis of prevalence of infection in children.

    Zheng, Qing Yu / Huynh, Kim T / van Zuylen, Wendy J / Craig, Maria E / Rawlinson, William D

    Reviews in medical virology

    2018  Band 29, Heft 1, Seite(n) e2011

    Abstract: Maternofetal transmission of cytomegalovirus (CMV) is the most common infectious cause of congenital malformation in developed countries. Maternal infection often results from close contact with infected children, and this may occur in day care centres ( ... ...

    Abstract Maternofetal transmission of cytomegalovirus (CMV) is the most common infectious cause of congenital malformation in developed countries. Maternal infection often results from close contact with infected children, and this may occur in day care centres (DCCs). A systematic review of observational studies was conducted to examine the prevalence of CMV infection among children attending DCCs. Meta-analysis using the random effect model was performed for studies including controls. Sources included PubMed, EMBASE (until August 2018), and references from identified publications. Inclusion criteria were studies reporting CMV infection prevalence among childcare children aged less than 7 years of age. Controls were children without childcare exposure. CMV infection was defined as viral excretion detected by culture, polymerase chain reaction, or CMV seropositivity. Twenty-eight publications including 8347 participants met the eligibility criteria. The pooled prevalence of CMV infection among children in childcare from all studies was 32% (95% CI 23-41). Within case-controlled studies, prevalence among children attending DCCs was 34% (95% CI 25-44), whereas prevalence among those without childcare exposure was 22% (95% CI 15-30). Meta-analysis showed a significant association between DCC attendance and CMV infection (odds ratio 2.69, 95% CI 1.68-4.30; heterogeneity χ
    Mesh-Begriff(e) Child ; Child Day Care Centers ; Child, Preschool ; Cytomegalovirus/isolation & purification ; Cytomegalovirus Infections/epidemiology ; Cytomegalovirus Infections/transmission ; Humans ; Infant ; Infant, Newborn ; Infection Control/methods ; Prevalence
    Sprache Englisch
    Erscheinungsdatum 2018-10-10
    Erscheinungsland England
    Dokumenttyp Journal Article ; Meta-Analysis ; Systematic Review
    ZDB-ID 1086043-5
    ISSN 1099-1654 ; 1052-9276
    ISSN (online) 1099-1654
    ISSN 1052-9276
    DOI 10.1002/rmv.2011
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Systematic review of ganciclovir pharmacodynamics during the prevention of cytomegalovirus infection in adult solid organ transplant recipients.

    Wong, Diana D / van Zuylen, Wendy J / Craig, Maria E / Rawlinson, William D

    Reviews in medical virology

    2018  Band 29, Heft 2, Seite(n) e2023

    Abstract: Human cytomegalovirus (CMV) represents the most common infection among recipients of solid organ transplants (SOTs). Previous meta-analysis showed 0.8% of SOT recipients developed CMV disease whilst receiving valganciclovir (ValGCV) prophylaxis. However, ...

    Abstract Human cytomegalovirus (CMV) represents the most common infection among recipients of solid organ transplants (SOTs). Previous meta-analysis showed 0.8% of SOT recipients developed CMV disease whilst receiving valganciclovir (ValGCV) prophylaxis. However, the clinical utility of monitoring ganciclovir (GCV) blood concentrations is unclear. We systematically reviewed the association between GCV concentrations during prophylaxis and the incidence of CMV. MEDLINE and EMBASE databases were searched for studies between 1946 and 2018, where GCV pharmacokinetics and incidence of CMV viraemia or disease in SOT were available. Research designs included randomised trials, comparative, prospective cohort, retrospective, or case report studies. Only human adult studies were included, with English language restriction. The 11 studies that met the eligibility criteria included 610 participants receiving GCV or ValGCV prophylaxis. Quality assessment showed 2/4 randomised trials, 4/6 cohort studies, and 1/1 case report were of high quality. Despite dose adjustments for renal impairment, mean GCV exposures for patients were heterogeneous and ranged between 28 and 53.7 μg·h/mL across three randomised trials. The incidence of CMV infection and disease ranged from 0% to 50% and 0% to 3.1%, respectively, with follow up between 3 to 9 months. One study showed statistical power in determining relationship, where GCV exposure at 40 to 50 μg·h/mL in high-risk SOT recipients was associated with a reduced risk of viraemia. Clinical monitoring for GCV exposure can be applied to high-risk SOT recipients during ValGCV prophylaxis; however, further studies are needed to determine the utility of monitoring in all SOT recipients.
    Mesh-Begriff(e) Adolescent ; Adult ; Aged ; Antiviral Agents/administration & dosage ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/pharmacology ; Base Composition ; Chemoprevention/methods ; Cytomegalovirus Infections/epidemiology ; Cytomegalovirus Infections/prevention & control ; Female ; Ganciclovir/administration & dosage ; Ganciclovir/pharmacokinetics ; Ganciclovir/pharmacology ; Humans ; Immunocompromised Host ; Incidence ; Male ; Middle Aged ; Organ Transplantation ; Prospective Studies ; Retrospective Studies ; Transplant Recipients ; Treatment Outcome ; Viremia/epidemiology ; Viremia/prevention & control ; Young Adult
    Chemische Substanzen Antiviral Agents ; Ganciclovir (P9G3CKZ4P5)
    Sprache Englisch
    Erscheinungsdatum 2018-12-17
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Systematic Review
    ZDB-ID 1086043-5
    ISSN 1099-1654 ; 1052-9276
    ISSN (online) 1099-1654
    ISSN 1052-9276
    DOI 10.1002/rmv.2023
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Comment on: Wnt5a inhibited human trophoblast cell line HTR8/SVneo invasion: implications for early placentation and preeclampsia.

    van Zuylen, Wendy J / Ford, Caroline E / Rawlinson, William D

    The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians

    2016  Band 30, Heft 9, Seite(n) 1085–1086

    Mesh-Begriff(e) Cell Line ; Female ; Humans ; Placentation ; Pre-Eclampsia ; Pregnancy ; Trophoblasts ; Wnt-5a Protein
    Chemische Substanzen WNT5A protein, human ; Wnt-5a Protein
    Sprache Englisch
    Erscheinungsdatum 2016-07-11
    Erscheinungsland England
    Dokumenttyp Journal Article ; Comment
    ZDB-ID 2077261-0
    ISSN 1476-4954 ; 1057-0802 ; 1476-7058
    ISSN (online) 1476-4954
    ISSN 1057-0802 ; 1476-7058
    DOI 10.1080/14767058.2016.1203411
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: Update on treatment of cytomegalovirus infection in pregnancy and of the newborn with congenital cytomegalovirus.

    Rawlinson, William D / Hamilton, Stuart T / van Zuylen, Wendy J

    Current opinion in infectious diseases

    2016  Band 29, Heft 6, Seite(n) 615–624

    Abstract: Purpose of review: The purpose of this review is to assess the recent studies of therapy of pregnant women and neonates, aimed at preventing the consequences of congenital cytomegalovirus (CMV) infection.: Recent findings: A recent randomized ... ...

    Abstract Purpose of review: The purpose of this review is to assess the recent studies of therapy of pregnant women and neonates, aimed at preventing the consequences of congenital cytomegalovirus (CMV) infection.
    Recent findings: A recent randomized controlled trial of treatment of CMV during pregnancy with hyperimmune globulin did not show significant efficacy in prevention of foetal infection and morbidity, although there was a trend towards improvement with treatment. Trials of antiviral therapy of the mother during pregnancy have involved small numbers only, confounded by ethical and practical difficulties, and further studies are needed to demonstrate whether or not antivirals are useful and well tolerated in this setting.Antiviral treatment of neonatal CMV acquired congenitally has been studied in well controlled trials and the antiviral valganciclovir has shown efficacy in reducing the more severe outcomes. Trials are ongoing of the use of antivirals in less severe disease, although results are likely to take several years.
    Summary: Congenital CMV infection is the most frequent cause of congenital malformation in developed countries, with a symptomatic prevalence of 0.64% of all live births. Infection may result in neurodevelopmental delay, foetal or neonatal death, and most frequently, sensorineural hearing loss. Successful control of viral infections during pregnancy and in the newborn period is essential in reducing early and late morbidity and mortality. Control of congenital CMV infection may be via primary prevention methods such as reducing contact with the pathogen, improved hygiene - both for the pregnant mother and for the neonate, or secondary prevention via reduction of vertical transmission from mother to foetus and reduction in consequences of infection by treatment of infected pregnant women and infected neonates.
    Mesh-Begriff(e) Cytomegalovirus ; Cytomegalovirus Infections/congenital ; Cytomegalovirus Infections/drug therapy ; Cytomegalovirus Infections/transmission ; Female ; Fetal Diseases/prevention & control ; Humans ; Immunoglobulins/therapeutic use ; Infant, Newborn ; Infectious Disease Transmission, Vertical/prevention & control ; Pregnancy ; Pregnancy Complications, Infectious/drug therapy ; Randomized Controlled Trials as Topic
    Chemische Substanzen Immunoglobulins
    Sprache Englisch
    Erscheinungsdatum 2016-10-17
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Review
    ZDB-ID 645085-4
    ISSN 1473-6527 ; 1535-3877 ; 0951-7375 ; 1355-834X
    ISSN (online) 1473-6527 ; 1535-3877
    ISSN 0951-7375 ; 1355-834X
    DOI 10.1097/QCO.0000000000000317
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: The Wnt pathway: a key network in cell signalling dysregulated by viruses.

    van Zuylen, Wendy J / Rawlinson, William D / Ford, Caroline E

    Reviews in medical virology

    2016  Band 26, Heft 5, Seite(n) 340–355

    Abstract: Viruses are obligate parasites dependent on host cells for survival. Viral infection of a cell activates a panel of pattern recognition receptors that mediate antiviral host responses to inhibit viral replication and dissemination. Viruses have evolved ... ...

    Abstract Viruses are obligate parasites dependent on host cells for survival. Viral infection of a cell activates a panel of pattern recognition receptors that mediate antiviral host responses to inhibit viral replication and dissemination. Viruses have evolved mechanisms to evade and subvert this antiviral host response, including encoding proteins that hijack, mimic and/or manipulate cellular processes such as the cell cycle, DNA damage repair, cellular metabolism and the host immune response. Currently, there is an increasing interest whether viral modulation of these cellular processes, including the cell cycle, contributes to cancer development. One cellular pathway related to cell cycle signalling is the Wnt pathway. This review focuses on the modulation of this pathway by human viruses, known to cause (or associated with) cancer development. The main mechanisms where viruses interact with the Wnt pathway appear to be through (i) epigenetic modification of Wnt genes; (ii) cellular or viral miRNAs targeting Wnt genes; (iii) altering specific Wnt pathway members, often leading to (iv) nuclear translocation of β-catenin and activation of Wnt signalling. Given that diverse viruses affect this signalling pathway, modulating Wnt signalling could be a generalised critical process for the initiation or maintenance of viral pathogenesis, with resultant dysregulation contributing to virus-induced cancers. Further study of this virus-host interaction may identify options for targeted therapy against Wnt signalling molecules as a means to reduce virus-induced pathogenesis and the downstream consequences of infection. Copyright © 2016 John Wiley & Sons, Ltd.
    Mesh-Begriff(e) Cell Cycle ; Cell Proliferation ; Epigenesis, Genetic ; Gene Expression Regulation ; Host-Pathogen Interactions ; Humans ; Immune Evasion ; MicroRNAs/metabolism ; Virus Diseases/immunology ; Virus Diseases/virology ; Viruses/immunology ; Viruses/pathogenicity ; Wnt Signaling Pathway
    Chemische Substanzen MicroRNAs
    Sprache Englisch
    Erscheinungsdatum 2016-09
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 1086043-5
    ISSN 1099-1654 ; 1052-9276
    ISSN (online) 1099-1654
    ISSN 1052-9276
    DOI 10.1002/rmv.1892
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel ; Online: Patient-Derived Cytomegaloviruses with Different Ganciclovir Sensitivities from UL97 Mutation Retain Their Replication Efficiency and Some Kinase Activity

    Wong, Diana D / van Zuylen, Wendy J / Hamilton, Stuart T / Steingruber, Mirjam / Sonntag, Eric / Marschall, Manfred / Rawlinson, William D

    Antimicrobial agents and chemotherapy

    2019  Band 63, Heft 9

    Abstract: Mutations in the cytomegalovirus UL97 kinase gene contribute to antiviral resistance. Mutations A594S and G598D from two clinical isolates were analyzed, and bacterial artificial chromosome (BAC)-engineered A594S recombinant cytomegalovirus exhibited a ... ...

    Abstract Mutations in the cytomegalovirus UL97 kinase gene contribute to antiviral resistance. Mutations A594S and G598D from two clinical isolates were analyzed, and bacterial artificial chromosome (BAC)-engineered A594S recombinant cytomegalovirus exhibited a ganciclovir-resistant phenotype on plaque reduction. Viral replication was comparable to that of the wild type. Cell-based kinase activity and autophosphorylation of ectopically expressed proteins showed that mutants retained some kinase activity. This study showed that patient-derived cytomegalovirus with different ganciclovir sensitivities retained replication efficiency and exhibited some kinase activity
    Mesh-Begriff(e) Antiviral Agents/pharmacology ; Cell Line ; Cell Line, Tumor ; Cytomegalovirus/drug effects ; Cytomegalovirus/enzymology ; Cytomegalovirus/genetics ; Drug Resistance, Viral/genetics ; Ganciclovir/pharmacology ; Humans ; Mutation/genetics ; Open Reading Frames/genetics ; Phosphorylation ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Virus Replication/drug effects ; Virus Replication/genetics
    Chemische Substanzen Antiviral Agents ; Protein Kinases (EC 2.7.-) ; Ganciclovir (P9G3CKZ4P5)
    Sprache Englisch
    Erscheinungsdatum 2019-08-23
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/AAC.02425-18
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: Role of IκB kinase-β in the growth-promoting effects of angiotensin II in vitro and in vivo.

    Doyon, Priscilla / van Zuylen, Wendy J / Servant, Marc J

    Arteriosclerosis, thrombosis, and vascular biology

    2013  Band 33, Heft 12, Seite(n) 2850–2857

    Abstract: Objective: Angiotensin II (Ang II) is implicated in processes underlying the development of arterial wall remodeling events, including cellular hypertrophy and inflammation. We previously documented the activation of IκB kinase-β (IKKβ) in Ang II- ... ...

    Abstract Objective: Angiotensin II (Ang II) is implicated in processes underlying the development of arterial wall remodeling events, including cellular hypertrophy and inflammation. We previously documented the activation of IκB kinase-β (IKKβ) in Ang II-treated cells, a kinase involved in inflammatory reactions. In light of a study suggesting a role of IKKβ in angiogenesis through its effect on the tuberous sclerosis (TSC)1/2-mammalian target of rapamycin complex 1 pathway in cancer cells, we hypothesized that targeting IKKβ could reduce arterial remodeling events by affecting both the inflammatory and the growth-promoting response of Ang II.
    Approach and results: Treatment of aortic vascular smooth muscle cells with Ang II induced the rapid and sustained phosphorylation of TSC1 on Ser511, which paralleled the activation of effectors of the mammalian target of rapamycin complex 1 pathway. Furthermore, we show that Ser511 of TSC1 acted as a phosphoacceptor site for Ang II-activated IKKβ. Consistent with this, the use of different short hairpin RNA constructs targeting IKKβ reduced Ang II-induced TSC1, S6 kinase, and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation and the rate of protein synthesis. Overexpression of TSC1 lacking Ser511 in vascular smooth muscle cells also exerted detrimental effects on the hypertrophic effect of Ang II. Furthermore, the selective IKKβ inhibitor N-(6-chloro-7-methoxy-9H-β-carbolin-8-yl)-2 methylnicotinamide reduced the inflammatory response and dose-dependently diminished Ang II-induced TSC1 phosphorylation and effectors of the mammalian target of rapamycin complex 1 pathway, leading to inhibition of protein synthesis in vitro and in rat arteries in vivo.
    Conclusions: Our findings provide new insights into the molecular understanding of the pathological role of Ang II and assist in identifying the beneficial effects of IKKβ inhibition for the treatment of cardiovascular diseases.
    Mesh-Begriff(e) Angiotensin II/administration & dosage ; Angiotensin II/pharmacology ; Animals ; Carrier Proteins/metabolism ; Cell Proliferation/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Hypertrophy ; I-kappa B Kinase/antagonists & inhibitors ; I-kappa B Kinase/genetics ; I-kappa B Kinase/metabolism ; Inflammation Mediators/metabolism ; Infusions, Subcutaneous ; Male ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes/metabolism ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/enzymology ; Muscle, Smooth, Vascular/pathology ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/enzymology ; Myocytes, Smooth Muscle/pathology ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Biosynthesis/drug effects ; RNA Interference ; Rats ; Rats, Sprague-Dawley ; Ribosomal Protein S6 Kinases/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Time Factors ; Transfection ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
    Chemische Substanzen Carrier Proteins ; Eif4ebp1 protein, rat ; Enzyme Inhibitors ; Inflammation Mediators ; Multiprotein Complexes ; Phosphoproteins ; Tumor Suppressor Proteins ; tuberous sclerosis complex 1 protein ; Angiotensin II (11128-99-7) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Ribosomal Protein S6 Kinases (EC 2.7.11.1) ; I-kappa B Kinase (EC 2.7.11.10)
    Sprache Englisch
    Erscheinungsdatum 2013-12
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1221433-4
    ISSN 1524-4636 ; 1079-5642
    ISSN (online) 1524-4636
    ISSN 1079-5642
    DOI 10.1161/ATVBAHA.113.302487
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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