Abstract
Extravillous cytotrophoblast (EVCT) is responsible for trophoblast invasion, which is important during placentation. Dysregulation of the process leads to pregnancy complications. S-nitrosylation of proteins is associated with cell invasion in many cell types. Adrenomedullin (ADM), a polypeptide expressed abundantly in the first-trimester placentas, induces EVCT invasion by upregulation of protein S-nitrosylation. This study aimed to identify the S-nitrosylated proteins induced by ADM in the JEG-3 placental cells. By using affinity chromatography followed by mass spectrometric analysis, tubulin, enolase, eukaryotic translation initiation factor 4A1, actin, annexin II (ANX II), and glyceraldehyde 3-phosphate dehydrogenaseprotein-1 were found to be S-nitrosylated by ADM. In vitro treatment with ADM or S-Nitrosoglutathione (GSNO) significantly increased the ANX II surface expression, but not its total expression in the JEG-3 cells. Translocation of ANX II to cell surface has been reported to act as a cell surface receptor to plasmin, plasminogen, and tissue plasminogen activator (tPA), thereby stimulating cell invasion and migration. However, in this study, ADM-induced surface expression of ANX II in the JEG-3 cells was not associated with changes in the secretory and membrane-bound tPA activities. Future studies are required to understand the roles of surface expression of S-nitrosylated ANX II on trophoblast functions. To conclude, this study provided evidences that ADM regulated the nitric oxide signaling pathway and modulated trophoblast invasion.
Highlights
During placental development, human trophoblasts differentiate along two cell lineages leading to the formation of extravillous cytotrophoblasts (EVCT) and villous cytotrophoblasts [1]
Data of this study suggested that ADM-induced Snitrosylation of annexin II (ANX II) and possibly other proteins in EVCT may take part in the regulation of EVCT invasion during early pregnancy
Both ADM and the GSNO treatment enhanced the invasion of EVCT and surface ANX II expression
Summary
Human trophoblasts differentiate along two cell lineages leading to the formation of extravillous cytotrophoblasts (EVCT) and villous cytotrophoblasts [1]. S-nitrosylation involves covalent attachment of a nitric oxide (NO) group to a cysteine thiol side chain. Protein Snitrosylation can either activate or inactivate protein function, depending on the protein nitosylated. S-nitrosylation of proteins has been associated with invasion in many cell types. In the human lung epithelial cell line, Beas-2B, stabilization of B-cell lymphoma (Bcl)-2 protein through S-nitrosylation leads to malignant transformation and increase in cell invasiveness [5]. In the MCF-7 breast cancer cells, β-estradiol
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