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Hyperglycemia impairs cytotrophoblast function via stress signaling.
Cawyer, Chase R; Horvat, Darijana; Leonard, Dean; Allen, Steven R; Jones, Richard O; Zawieja, David C; Kuehl, Thomas J; Uddin, Mohammad N.
Afiliação
  • Cawyer CR; Department of Obstetrics and Gynecology, Scott and White Healthcare/Texas A&M Health Science Center College of Medicine, Temple, TX.
  • Horvat D; Department of Obstetrics and Gynecology, Scott and White Healthcare/Texas A&M Health Science Center College of Medicine, Temple, TX.
  • Leonard D; Prehealth Studies, Baylor University, Waco, TX.
  • Allen SR; Department of Obstetrics and Gynecology, Scott and White Healthcare/Texas A&M Health Science Center College of Medicine, Temple, TX.
  • Jones RO; Department of Obstetrics and Gynecology, Scott and White Healthcare/Texas A&M Health Science Center College of Medicine, Temple, TX.
  • Zawieja DC; Department of Medical Physiology, Scott and White Healthcare/Texas A&M Health Science Center College of Medicine, Temple, TX.
  • Kuehl TJ; Department of Obstetrics and Gynecology, Scott and White Healthcare/Texas A&M Health Science Center College of Medicine, Temple, TX.
  • Uddin MN; Department of Obstetrics and Gynecology, Scott and White Healthcare/Texas A&M Health Science Center College of Medicine, Temple, TX. Electronic address: mnuddin@sw.org.
Am J Obstet Gynecol ; 211(5): 541.e1-8, 2014 Nov.
Article em En | MEDLINE | ID: mdl-24793974
OBJECTIVE: Diabetes mellitus is a risk factor for preeclampsia. Cytotrophoblast (CTB) invasion is facilitated from the conversion of plasminogen to plasmin by urokinase plasminogen activator (uPA), regulated by plasminogen activator inhibitor 1 (PAI-1), and may be inhibited in preeclampsia. This study assessed signaling mechanisms of hyperglycemia-induced CTB dysfunction. STUDY DESIGN: Human CTBs were treated with 45, 135, 225, 495, or 945 mg/dL glucose for 48 hours. Some cells were pretreated with a p38 inhibitor (SB203580) or a peroxisome proliferator-activated receptor-gamma (PPAR-γ) ligand (rosiglitazone). Expression of uPA, PAI-1, and PPAR-γ levels and p38 mitogen-activated protein kinase phosphorylation were measured by Western blot in cell lysates. Messenger ribonucleic acid of uPA and PAI-1 was measured by quantitative polymerase chain reaction. Levels of interleukin-6, angiogenic (vascular endothelial growth factor [VEGF], placenta growth factor [PlGF]) and antiangiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], soluble endoglin [sEng]) were measured in the media by enzyme-linked immunosorbent assay kits. Statistical comparisons were performed using analysis of variance with a Duncan's post-hoc test. RESULTS: Both uPA and PAI-1 protein and messenger ribonucleic acid were down-regulated (P < .05) in CTBs treated with 135 mg/dL glucose or greater compared with basal (45 mg/dL). The sEng, sFlt-1, and interleukin-6 were up-regulated, whereas the VEGF and PlGF were down-regulated by 135 mg/dL glucose or greater. p38 phosphorylation and PPAR-γ were up-regulated (P < .05) in hyperglycemia-treated CTBs. The SB203580 or rosiglitazone pretreatment showed an attenuation of glucose-induced down-regulation of uPA and PAI-1. CONCLUSION: Hyperglycemia disrupts the invasive profile of CTB by decreasing uPA and PAI-1 expression; down-regulating VEGF and PlGF; and up-regulating sEng, sFlt-1, and interleukin-6. Attenuation of CTB dysfunction by SB203580 or rosiglitazone pretreatment suggests the involvement of stress signaling.
Assuntos
Glucose/farmacologia; Hiperglicemia/metabolismo; Inibidor 1 de Ativador de Plasminogênio/genética; Trofoblastos/efeitos dos fármacos; Ativador de Plasminogênio Tipo Uroquinase/efeitos dos fármacos; Antígenos CD/efeitos dos fármacos; Antígenos CD/metabolismo; Diabetes Gestacional/metabolismo; Endoglina; Ensaio de Imunoadsorção Enzimática; Feminino; Humanos; Hipoglicemiantes/farmacologia; Imidazóis/farmacologia; Interleucina-6/metabolismo; PPAR gama/efeitos dos fármacos; PPAR gama/metabolismo; Fosforilação/efeitos dos fármacos; Fator de Crescimento Placentário; Inibidor 1 de Ativador de Plasminogênio/metabolismo; Reação em Cadeia da Polimerase; Gravidez; Proteínas da Gravidez/efeitos dos fármacos; Proteínas da Gravidez/metabolismo; Piridinas/farmacologia; Receptores de Superfície Celular/efeitos dos fármacos; Receptores de Superfície Celular/metabolismo; Rosiglitazona; Transdução de Sinais/efeitos dos fármacos; Tiazolidinedionas/farmacologia; Ativador de Plasminogênio Tipo Uroquinase/genética; Ativador de Plasminogênio Tipo Uroquinase/metabolismo; Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos; Fator A de Crescimento do Endotélio Vascular/metabolismo; Receptor 1 de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos; Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo; Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores; Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos; Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trofoblastos / Ativador de Plasminogênio Tipo Uroquinase / Inibidor 1 de Ativador de Plasminogênio / Glucose / Hiperglicemia Tipo de estudo: Risk_factors_studies Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trofoblastos / Ativador de Plasminogênio Tipo Uroquinase / Inibidor 1 de Ativador de Plasminogênio / Glucose / Hiperglicemia Tipo de estudo: Risk_factors_studies Idioma: En Ano de publicação: 2014 Tipo de documento: Article