title: Simvastatin inhibits oxidative stress via the activation of nuclear factor erythroid 2-related factor 2 signaling in trophoblast cells.
abstract: OBJECTIVE
  Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator against oxidative stress through the induction of antioxidant and cytoprotective genes, such as heme oxygenase 1 (HO-1), glutamyl cysteine ligase catalytic (GCLC), and glutamyl cysteine ligase modulatory (GCLM). Nrf2 signaling is disrupted in pre-eclamptic placentas, although increased oxidative stress is implicated in pre-eclampsia. The aims of the study were: (i) to investigate the mechanism that underlies the impaired Nrf2 signaling in pre-eclamptic placentas, and (ii) to examine the potential therapeutic role of statin for pre-eclampsia.
  
  
  METHODS
  Human choriocarcinoma JAR cells were cultured under normoxia (20% O2 ) or hypoxia (1% O2 ). Small-interfering ribonucleic acids were used to knockdown Nrf2. Real-time quantitative reverse transcriptase polymerase chain reaction and Western blotting were used to evaluate the influence of oxidative stress (H2O2 100 μM) and simvastatin (50 μM) on Nrf2 and its target genes. Reactive oxygen species levels were analyzed by flow cytometry in immortalized human trophoblast TCL1 cells treated with or without H2O2 (100 μM) ± simvastatin (50 μM).
  
  
  RESULTS
  Nuclear factor erythroid 2-related factor 2 activation was significantly suppressed under hypoxic conditions. Nrf2 knockdown resulted in insufficient enhancement of HO-1, GCLC and GCLM expression under oxidative stress. In contrast, Nrf2 signaling was augmented by simvastatin, which suppressed the induction of oxidative stress in trophoblasts.
  
  
  CONCLUSIONS
  Hypoxia is one of the important negative regulators of Nrf2 activation, and simvastatin inhibits oxidative stress through the activation of Nrf2 signaling in trophoblasts, indicating the potential therapeutic role of statin for pre-eclampsia.
authors.affiliation: Department of Gynecology and Obstetrics Graduate School of Medicine, Kyoto University, Koyo, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Chigusa
authors.affiliation: Department of Gynecology and Obstetrics Graduate School of Medicine, Kyoto University, Koyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kawasaki
authors.affiliation: Department of Gynecology and Obstetrics Graduate School of Medicine, Kyoto University, Koyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kondoh
authors.affiliation: Department of Gynecology and Obstetrics Graduate School of Medicine, Kyoto University, Koyo, Japan.
authors.forename: Haruta
authors.initials: H
authors.lastname: Mogami
authors.affiliation: Department of Gynecology and Obstetrics Graduate School of Medicine, Kyoto University, Koyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ujita
authors.affiliation: Department of Gynecology and Obstetrics Graduate School of Medicine, Kyoto University, Koyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Gynecology and Obstetrics Graduate School of Medicine, Kyoto University, Koyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Gynecology and Obstetrics Graduate School of Medicine, Kyoto University, Koyo, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051267:NF-E2-Related Factor 2; D019821:Simvastatin
keywords: Nrf2; hypoxia; oxidative stress; pre-eclampsia; statin