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.
Highlights
Pre-eclampsia (PE), a pregnancy-specific disease accounting for pregnancy complications of 5% to 7%, is one of the most common reason for high morbidity and mortality of maternal and perinatal infants [1]
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 confirmed in human placenta tissues
Summary
Pre-eclampsia (PE), a pregnancy-specific disease accounting for pregnancy complications of 5% to 7%, is one of the most common reason for high morbidity and mortality of maternal and perinatal infants [1]. Inhibitor of DNA binding (ID) family protein is a class of transcription factors, including ID1 / 2/3/4 They play an important role in the regulation of endothelial cell cycle, proliferation, migration and angiogenesis and invasion [4]. Prostacyclin can inhibit the proliferation of smooth muscle cells, thereby preventing the progression of pulmonary hypertension and increase Smad1/5 phosphorylation and Id1 expression [8]. The study found that TGFβ/Smad pathway plays an important role in vascular endothelial cells, inhibition of Smad6/7 can antagonize TGFβ-induced pulmonary artery endothelial cell permeability disorder [9]. In the early stage of eclampsia, the expression of Smad phosphorylation and Smad in placental tissue is increased and plays an important role in the proliferation and differentiation of trophoblast cells [11]
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