lithium-chloride and Pre-Eclampsia

Preeclampsia (PE) is characterized by abnormal placentation in the early stages of pregnancy. Adequate migration and invasion of trophoblasts into the uterine wall and spiral arteries to form a functional maternal-fetal interface are pivotal for normal placentation, but the exact mechanism remains unclear. Growing evidence has revealed that special AT-rich sequence binding protein 1 (binds to nuclear matrix/scaffold-associating DNA) (SATB1) is a tumor promoter that participates in cancer cell migration and invasion. However, the expression and function of SATB1 in trophoblasts is unknown. Here, we characterize the stimulatory effect of SATB1 on the migration and invasion of trophoblasts and identify the regulatory events and downstream signaling components. Downregulated SATB1 was detected in PE placentae and villous explants cultured under hypoxia/reoxygenation (H/R) conditions. H/R-treated trophoblasts with lower SATB1 levels exhibited weaker invasive and growth capacities, whereas upregulation of the SATB1 level with recombinant SATB1 restored these impairments. This restoration was especially apparent with the sumoylation-deficient SATB1 variant, which contained a mutated site that blocked sumoylation. Moreover, the elevated concentration of SATB1 also increased the expression of β-catenin, which is involved in human placental trophoblast invasion and differentiation is downregulated in PE. However, a specific activator, namely, lithium chloride (LiCl), increased β-catenin expression but had no evident influence on SATB1 expression. Furthermore, upregulated SATB1 failed to restore trophoblast function when Wnt/β-catenin was suppressed by dickkopf (Xenopus laevis) homolog 1, dickkopf 1 homolog (Xenopus laevis) (DKK1). Together, these data show that SATB1expression in the human placenta is affected by oxidative stress and might regulate the migration and invasion of trophoblasts via β-catenin signaling.

Topics: beta Catenin; Cell Movement; Down-Regulation; Female; Humans; Hypoxia; Lithium Chloride; Matrix Attachment Region Binding Proteins; Oxidative Stress; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Signal Transduction; Trophoblasts

Preeclampsia is a major pregnancy-specific disorder affecting 5-7% of pregnancies worldwide. Although hypoxia caused by incomplete trophoblast invasion and impaired spiral arterial remodeling is thought to be a major cause of preeclampsia, how hypoxia affects placental development remains uncertain. GCM1 (glial cells missing homolog 1) is a transcription factor critical for placental development. In preeclampsia, GCM1 and its target genes syncytin 1 and placental growth factor, important for syncytiotrophoblast formation and placental vasculogenesis, are all decreased. Here we present evidence that GCM1 is a major target of hypoxia associated with preeclampsia. We show that hypoxia triggers GCM1 degradation by suppressing the phosphatidylinositol 3-kinase-Akt signaling pathway, leading to GSK-3beta activation. Activated GSK-3beta phosphorylates GCM1 on Ser322, which in turn recruits the F-box protein FBW2, leading to GCM1 ubiquitination and degradation. Importantly, the GSK-3beta inhibitor LiCl prevented hypoxia-induced GCM1 degradation. Our study identifies a molecular basis for the disrupted GCM1 transcription network in preeclampsia and provides a potential avenue for therapeutic intervention.

Topics: Antimanic Agents; Cells, Cultured; DNA-Binding Proteins; Female; Fluorescent Antibody Technique; Gene Products, env; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Hypoxia; Immunoblotting; Immunoenzyme Techniques; Immunoprecipitation; Lithium Chloride; Nuclear Proteins; Phosphatidylinositol 3-Kinases; Phosphorylation; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; SKP Cullin F-Box Protein Ligases; Transcription Factors; Transfection; Ubiquitination