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Alpha-1-antitrypsin functions as a protective factor in preeclampsia through activating Smad2 and inhibitor of DNA
Yaling Feng1, Nan Wang2, Jianjuan Xu1
1Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, PR China.
Insights
Alpha-1-antitrypsin (AAT) protects against pre-eclampsia by activating the Smad2/Id4 pathway, improving antioxidant defense and placental function. This discovery offers new insights into managing pregnancy-associated disorders.
Area of Science:
- Obstetrics and Gynecology
- Molecular Biology
- Pathophysiology
Background:
- Pre-eclampsia (PE) is a leading cause of maternal and infant morbidity/mortality.
- Oxidative stress in PE disrupts antioxidant systems, leading to tissue damage.
- Previous studies indicated Alpha-1-antitrypsin (AAT) has protective effects in PE models.
Purpose of the Study:
- To elucidate the molecular mechanism by which AAT mitigates pre-eclampsia progression.
- To identify genes and pathways regulated by AAT in the context of PE.
Main Methods:
- Whole-exome sequencing to identify AAT-altered genes.
- In vitro studies using human umbilical vein endothelial cells (HUVECs) under hypoxia-reoxygenation.
- Analysis of Smad and Id gene family expression.
- Validation in a pre-eclampsia animal model and human placental tissues.
Main Results:
- AAT positively regulates Id4 expression via Smad2 activation.
- AAT knockdown altered Smad and Id gene expression.
- Reduced Id4 expression and Smad2 phosphorylation were observed in PE models and human tissues.
- AAT protected HUVECs from injury and alleviated PE symptoms through the Smad2/Id4 axis.
Conclusions:
- The AAT/Smad2/Id4 axis is crucial for placental and vascular function during pregnancy.
- This pathway represents a potential therapeutic target for pre-eclampsia.
- Findings enhance understanding of pregnancy-associated disorders.
Abstract:
Pre-eclampsia (PE) is one of the most common reason for high morbidity and mortality of maternal and prenatal infants. Production from oxidative stress results in maternal ROS system and anti-oxidation defense system imbalance to promote tissue ischemia and hypoxia, and ultimately impairs the maternal organs and placenta. Our previous study showed that exogenous Alpha-1-antitrypsin (AAT) and overexpression of AAT in umbilical vein cell (HUVEC) hypoxia-reoxygenation model could increase the activity of antioxidant enzymes, and played a protective role in preeclampsia animal model. In this study, we aim to investigate the underlying mechanism by which AAT prevents PE progress. Whole-exome sequencing was performed to screen the genes altered by AAT. We found that AAT knockdown altered the expression of Smad family and Id family genes, and further demonstrated that AAT positively regulated Id4 expression through activating Smad2. Reduced Id4 expression and Smad2 phosphorylation were observed in preeclampsia animal model, which was also confirmed in human placenta tissues. In addition, AAT protected HUVEC cells from hypoxia/reoxygenation injury and relieved preeclampsia symptoms through Smad2/Id4 axis. Our data illustrate AAT/Smad2/Id4 axis is an important mediator of placenta and vascular function during pregnancy. These findings provide insights into events governing pregnancy-associated disorders, such as preeclampsia.
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