TWIST1 Alleviates Hypoxia-induced Damage of Trophoblast Cells by inhibiting mitochondrial apoptosis pathway

Abstract Preeclampsia (PE), especially severe and early-onset preeclampsia is one of the major causes of maternal and neonatal morbidity and mortality. However, the exact mechanism is not fully understood. In this study, we first demonstrated that the expression of TWIST1 was decreased in the placental tissues of patients with early-onset severe preeclampsia, compared with non-severe early onset preeclampsia. In hypoxia-treated HTR-8/SVneo cells, our study showed that TWIST1 expression was significantly decreased. Moreover, TWIST1 overexpression reduced apoptosis and enhanced invasion and tube formation of HTR-8/SVneo cells while TWIST1 knockdown showed the opposite results. Mechanistically, TWIST1 inhibited apoptosis by blocking the activation of mitochondrial apoptosis signaling Bax/Bcl-2/Caspase-9/Caspase-3, which was confirmed by the use of Caspase-9 activator and inhibitor. This was in line with the reduced ROS formation and the decreased mitochondrial transmembrane potential. On the other hand, TWIST1 increased the ability of migration and invasion of HTR-8/SVneo cells via enhancements of MMP-2/9 expression. Taken together, for the first time we show that TWIST1 plays an important role in the survival, invasion and tube formation of-HTR8/SVneo cells treated with hypoxia. This hypoxia-treated cell model partly mimics the in vivo condition of decreased placental perfusion induced by H/R. Thus, our study provides an important clue about TWIST1 molecular mechanism underlying the development of preeclampsia.