SIRT3 deficiency affects the migration, invasion, tube formation and necroptosis of trophoblast and is implicated in the pathogenesis of preeclampsia.

Abstract

Sirtuin 3 (SIRT3) plays a key role in many diseases by regulating cell necroptosis and biological behavior. However, the exact role of SIRT3 in preeclampsia remains unclear. The expression of SIRT3 and necroptosis biomarkers, including receptor-interacting protein kinase 1 (RIPK1), RIPK3 and phosphorylated mixed lineage kinase domain-like protein (p-MLKL), in the placentas of 20 healthy pregnancy controls and 20 preeclampsia patients was evaluated by immunofluorescence, quantitative real-time PCR and Western blot. The effect of hypoxia on trophoblast necroptosis was examined in HTR8/SVneo cells. The effects of SIRT3 on the necroptosis, invasion, migration, and tube formation of HTR8/SVneo cells were investigated by transfection with siRNA lentiviruses that silenced or overexpressed SIRT3. The expression of SIRT3 was decreased and the expression of RIPK1, RIPK3 and p-MLKL was increased in placental trophoblasts from preeclampsia patients compared to those from healthy pregnancy controls. Hypoxia increased RIPK1, RIPK3 and p-MLKL expression in HTR8/SVneo cells, while necrostatin-1 pretreatment reduced RIPK1, RIPK3 and p-MLKL expression in HTR8/SVneo cells under hypoxia. SIRT3 silencing increased RIPK1, RIPK3 and p-MLKL expression and inhibited the invasion, migration, and tube formation of HTR8/SVneo cells under hypoxia. SIRT3 overexpression produced the opposite results. We report that SIRT3 deficiency may be involved in the pathogenesis of preeclampsia by increasing necroptosis and causing abnormal trophoblastic biological behavior. The underlying mechanisms need further study.