Regulator of G protein signaling 2 is inhibited by hypoxia-inducible factor-1α/E1A binding protein P300 complex upon hypoxia in human preeclampsia

Background: Preeclampsia is a pregnancy-related complication that causes maternal and fetal mortality. Despite extensive studies showing the role of hypoxia in preeclampsia progression, the specific mechanism remains unclear. The purpose of this study was to explore the possible mechanism underlying hypoxia in preeclampsia. Methods: Human trophoblast-like JEG-3 cell line was used to investigate the molecular mechanisms underlying hypoxia contribution to preeclampsia and the expression correlation of key molecules was examined in human placental tissues. Methods include JEG-3 cell culture and hypoxia induction, RNA isolation and quantitative realtime PCR, transient transfection and dual-luciferase assay, western blot, immunoprecipitation, immunofluorescence staining, cell proliferation assay, chromatin immunoprecipitation assay, obtainment of human placental tissue sample and immunohistochemistry staining. Results: Hypoxia-Inducible Factor-1 alpha is up-regulated in clinical preeclampsia samples, where Regulator of G Protein Signaling 2 is down-regulated. Mechanistically, Hypoxia-Inducible Factor-1 alpha is induced in response to hypoxia, which up-regulates E1A binding protein P300 expression and thereby forms a Hypoxia-Inducible Factor-1 alpha/E1A binding protein P300 protein-protein complex that binds to the promoter of gene Regulator of G Protein Signaling 2 and subsequently inhibits the transcription of Regulator of G Protein Signaling 2, possibly contributing to the preeclampsia development. In addition, the expression of E1A binding protein P300 is increased in preeclampsia samples, and the expression of Regulator of G Protein Signaling 2 in preeclamptic placentas inversely correlates with the levels of E1A binding protein P300. Conclusion: Our findings may provide novel insights into understanding the molecular pathogenesis of preeclampsia and may be a prognostic biomarker and therapeutic target for preeclampsia.

Automated summary

The study discovered that Hypoxia-Inducible Factor-1 alpha is up-regulated in clinical preeclampsia samples, while Regulator of G Protein Signaling 2 is down-regulated. Mechanistically, Hypoxia-Inducible Factor-1 alpha is induced in response to hypoxia, forming a complex with E1A binding protein P300 that inhibits the transcription of Regulator of G Protein Signaling 2, potentially contributing to the development of preeclampsia.