Alpha-1-antitrypsin functions as a protective factor in preeclampsia through activating Smad2 and inhibitor of DNA binding 4

// Yaling Feng 1, * , Nan Wang 2, * , Jianjuan Xu 1 , Jinfang Zou 1 , Xi Liang 1 , Huan Liu 1 and Ying Chen 3 1 Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, PR China 2 Department of Obstetrics, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, PR China 3 Central Lab, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, PR China * These authors have contributed equally to this work Correspondence to: Yaling Feng, email: 15161506909@163.com Ying Chen, email: 13600182648@163.com Keywords: pre-eclampsia; alpha-1-antitrypsin; Smad; inhibitor of DNA binding; whole-exome sequencing Received: September 16, 2017      Accepted: November 13, 2017      Published: December 05, 2017 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.