Oxidative stress-induced Gadd45α inhibits trophoblast invasion and increases sFlt1/sEng secretions via p38 MAPK involving in the pathology of pre-eclampsia. (1st December 2016)

• Record Type: Journal Article
• Authors: Liu, Xiru; Deng, Qinyin; Luo, Xin; Chen, Ying; Shan, Nan; Qi, Hongbo
• Is Part Of: Journal of maternal-fetal & neonatal medicine. Volume 29:Number 23(2016)
• Page Start: 3776
• Page End: 3785
• Publication Date: 2016-12-01
• Subjects: Growth arrest and DNA damage-inducible 45α -- pre-eclampsia -- soluble endoglin -- soluble Fms-like tyrosine kinase 1 -- trophoblast invasion; Obstetrics -- Periodicals; Perinatology -- Periodicals; Infants (Newborn) -- Diseases -- Periodicals; Neonatology -- Periodicals; 618.2
• DOI: 10.3109/14767058.2016.1144744
• Languages: English
• ISSNs: 1476-7058

Abstract

Abstract: Background : Pre-eclampsia (PE) is one of the most common pregnancy-related complications. We have previously reported that growth arrest and DNA damage-inducible 45 alpha (Gadd45α) is over-expressed in trophoblasts in pre-eclamptic placentas, with an excessive activation of p38 mitogen-activated protein kinase (MAPK) and increased levels of soluble Fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) in maternal sera. Now we further investigate how Gadd45α regulates trophoblast functions and anti-angiogenesis factors secretions during placental development in patients with PE. Methods : Human placental villous explants were used to verify the effects of Gadd45α and p38 MAPK in placentation. Then HRT8/SVneo cells exposed to hypoxia/reoxygenation (H/R) were employed as an oxidative stress model to investigate the effects of Gadd45α on invasion and sFlt-1/sEng secretions. Through silencing Gadd45α with lentiviral vector-based short-hairpin RNA and inhibiting p38 MAPK with SB203580, we demonstrated that Gadd45α and its downstream p38 protein played roles in the pathology of pre-eclampsia. Results : Gadd45α was found to have increased expression in H/R-treated villous explants and HTR8/SVneo cells. Gadd45α knockdown or p38 blockage could promote trophoblast outgrowth and migration in H/R-exposed villous explants, and enhance the potentials of trophoblast migration/invasion and network formation in H/R-exposed HTR8/SVneo cells. These functional changes might be related to the increased activities of MMP2/9. Meanwhile, Gadd45α knockdown or p38 inhibition also decreases sFlt-1/sEng secretions via suppressing oxidative stress. Conclusions : Oxidative stress-induced overexpression of Gadd45α might influence the activity of MMPs through activation of p38 MAPK signaling to affect the invasion of trophoblast cells, and increase the secretions of sFlt-1/sEng, which then participate in the pathogenesis of pre-eclampsia.