Simvastatin inhibits oxidative stress via the activation of nuclear factor erythroid 2‐related factor 2 signaling in trophoblast cells

Chigusa, Yoshitsugu; Kawasaki, K.; Kondoh, Eiji; Mogami, Haruta; Ujita, Mari; Fujita, Kohei; Tatsumi, Kazuyoshi; Takeda, Satoru; Konishi, Ikuo

doi:10.1111/jog.12876

Cited by 13 publications

(7 citation statements)

References 33 publications

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“…Indeed, HMOX1 expression is decreased in placentas with preeclampsia (Chigusa et al, ) and in hypoxia‐induced trophoblasts (Ahmed et al, ). Furthermore, lower HMOX1 abundance is associated with lower cell motility and invasiveness (Bilban et al, ), whereas increasing its expression amended oxidative stress injuries in trophoblasts (Chigusa et al, ).…”

Section: Discussionmentioning

confidence: 99%

Edaravone protects against cobalt chloride‐induced dysfunctions in apoptosis and invasion in trophoblast cells

Zheng

Zhao

Luo

et al. 2016

Molecular Reproduction Devel

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This study was performed to investigate the effects of edaravone on hypoxia-induced trophoblast cell proliferation, apoptosis, and invasion. The trophoblast cell line HTR-8 (H8) was treated with cobalt chloride (CoCl2 ) with or without a 1-hr edaravone pretreatment, followed by assessment of intracellular reactive oxygen species (ROS) levels, cell proliferation, apoptosis, migration, and invasion. Metrics of apoptosis included measurement of cysteine-aspartic acid protease 3 (CASP3) activity as well as BAX and BCL2 expression. Migration and invasion phenotypes were complemented with expression analysis of matrix metalloproteinase 2 (MMP2) and tissue inhibitor of metalloproteinase 2 (TIMP2) at the transcript and protein levels. CoCl2 inhibited the proliferation of H8 cells, promoted apoptosis, and up-regulated CASP3 activation and BAX expression while inhibiting BCL2 expression. CoCl2 treatment also reduced the invasiveness of H8 cells by inhibiting MMP2 activity. Edaravone significantly increased H8 cell proliferation; inhibited apoptosis by down-regulating CASP3 activation and BAX production while promoting BCL2 stability; and ameliorated the migration and invasion phenotypes associated with CoCl2 treatment. These results suggest that edaravone may rescue hypoxia-induced abnormalities in H8 cell proliferation, apoptosis, and invasion, thereby protecting the trophoblast lineage against hypoxia. Mol. Reprod. Dev. 83: 576-587, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Edaravone protects against cobalt chloride‐induced dysfunctions in apoptosis and invasion in trophoblast cells

Zheng

Zhao

Luo

et al. 2016

Molecular Reproduction Devel

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“…It was recently shown that antioxidant ursodeoxycholic acid prevents acute aortic dissection via activation of Nrf2 and Nrf2-regulated antioxidant redox enzymes in aortic VSMC [ 12 ]. Furthermore, Nrf2 activation that leads to the higher expression of HMOX1 is regulated by oxidative stress and can be augmented by therapeutic agents such as statins [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

Piechota-Polańczyk

Kopacz

Klóska

et al. 2018

Oxidative Medicine and Cellular Longevity

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Heme oxygenase-1 (HO-1), encoded by HMOX1 gene and regulated by Nrf2 transcription factor, is a cytoprotective enzyme. Its deficiency may exacerbate abdominal aortic aneurysm (AAA) development, which is also often associated with hyperlipidemia. Beneficial effects of statins, the broadly used antilipidemic drugs, were attributed to modulation of Nrf2/HO-1 axis. However, the effect of statins on Nrf2/HO-1 pathway in patients with AAA has not been studied yet. We analyzed AAA tissue from patients treated with simvastatin (N = 28) or without statins (N = 14). Simvastatin treatment increased HO-1 protein level in AAA, both in endothelial cells (ECs) and in smooth muscle cells (SMCs), but increased Nrf2 localization was restricted only to vasa vasorum. Nrf2 target genes HMOX1, NQO1, and GCLM expression remained unchanged in AAA. In vitro studies showed that simvastatin raises HO-1 protein level slightly in ECs and to much higher extent in SMCs, which is not related to Nrf2/ARE activation, although HMOX1 expression is upregulated by simvastatin in both cell types. In conclusion, simvastatin-induced modulation of HO-1 level in ECs and SMCs in vitro is not related to Nrf2/ARE activity. Likewise, divergent HO-1 and Nrf2 localization together with stable expression of Nrf2 target genes, including HMOX1, in AAA tissue denotes Nrf2 independency.

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“…Simvastatin may be a more potent inhibitor of sFlt-1 secretion from endothelial cells, trophoblast cells, and placenta from women with preterm preeclampsia than either pravastatin or rosuvastatin (24). In a human cell line (Human choriocarcinoma JAR cells), simvastatin reduces oxidative stress, which is the reason it can potentially play a role in the treatment of preeclampsia (25). Simvastatin treatment significantly decreased hypertension, sFlt-1, TNF-α, and oxidative stress marker malondialdehyde levels in a preeclampsia rat model (NG-nitro-L-arginine methyl ester-induced) (26).…”

Section: Choice Of Pravastatinmentioning

confidence: 99%

Pravastatin in preeclampsia: A meta-analysis and systematic review

Mészáros

Veres²,

Nagyistók³

et al. 2023

Front. Med.

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ObjectiveTo review of the efficacy and safety of pravastatin use for prophylaxis and treatment of preeclampsia.DesignSystematic review and meta-analysis of clinical studies evaluating pravastatin for treatment and/or prophylaxis of preeclampsia.Data collectionTwo independent reviewers systematically searched data from PubMed, Scopus, Web of Science, Cochrane, Embase, and clinicaltrials.gov databases, for studies evaluating pravastatin for prevention of pre-eclampsia.ResultsFourteen studies were identified, including 1,570 pregnant women who received either pravastatin or placebo, published between 2003 and 2022. From these studies, 5 studies were identified for inclusion in the meta-analysis to evaluate the role of pravastatin use prior to 20 weeks of gestation, to prevent pre-eclampsia, Pravastatin treatment reduced the incidence of preeclampsia by 61% and premature birth by 45%. Among the newborns, there was a 45% reduction in intrauterine growth retardation (IUGR) in the treated group, as well as a 77% reduction in those receiving neonatal intensive care unit (NICU) admissions.ConclusionProphylactic treatment with pravastatin appears to reduce risk of developing pre-eclampsia as well as potentially lowering risk of IUGR, preterm birth, and NICU admission in neonates.

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Simvastatin inhibits oxidative stress via the activation of nuclear factor erythroid 2‐related factor 2 signaling in trophoblast cells

Abstract: 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.

Cited by 13 publications

References 33 publications

Edaravone protects against cobalt chloride‐induced dysfunctions in apoptosis and invasion in trophoblast cells

Edaravone protects against cobalt chloride‐induced dysfunctions in apoptosis and invasion in trophoblast cells

Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

Pravastatin in preeclampsia: A meta-analysis and systematic review

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