Oxidative stress-induced Gadd45α inhibits trophoblast invasion and increases sFlt1/sEng secretions via p38 MAPK involving in the pathology of pre-eclampsia
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians - 29(2016), 23 vom: 24. Dez., Seite 3776-85 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Xiru [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.06.2017 Date Revised 14.06.2017 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.3109/14767058.2016.1144744 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM256823618 |
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| 245 | 1 | 0 | |a Oxidative stress-induced Gadd45α inhibits trophoblast invasion and increases sFlt1/sEng secretions via p38 MAPK involving in the pathology of pre-eclampsia |
| 264 | 1 | |c 2016 | |
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| 500 | |a Date Revised 14.06.2017 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Growth arrest and DNA damage-inducible 45α | |
| 650 | 4 | |a pre-eclampsia | |
| 650 | 4 | |a soluble Fms-like tyrosine kinase 1 | |
| 650 | 4 | |a soluble endoglin | |
| 650 | 4 | |a trophoblast invasion | |
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| 650 | 7 | |a ENG protein, human |2 NLM | |
| 650 | 7 | |a Endoglin |2 NLM | |
| 650 | 7 | |a Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a GADD45A protein, human |2 NLM | |
| 650 | 7 | |a Imidazoles |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
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| 650 | 7 | |a p38 Mitogen-Activated Protein Kinases |2 NLM | |
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| 650 | 7 | |a SB 203580 |2 NLM | |
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| 700 | 1 | |a Deng, Qinyin |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Shan, Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Hongbo |e verfasserin |4 aut | |
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