Yu Hongbiao, Zhang Yanping, Liu Min, Liao Lingyun, Wei Xiaohong, Zhou Rong
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) of Ministry of Education, Chengdu, Sichuan, China; Department of Obstetrics and Gynecology, Nanchong Central Hospital, Nanchong, Sichuan, China.
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) of Ministry of Education, Chengdu, Sichuan, China.
Placenta. 2022 Mar 24;120:1-9. doi: 10.1016/j.placenta.2022.01.014. Epub 2022 Jan 24.
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.
沉默调节蛋白3（SIRT3）通过调节细胞坏死性凋亡和生物学行为在多种疾病中起关键作用。然而，SIRT3在子痫前期的确切作用仍不清楚。
通过免疫荧光、定量实时PCR和蛋白质免疫印迹法评估20例健康妊娠对照组和20例子痫前期患者胎盘组织中SIRT3及坏死性凋亡生物标志物的表达，包括受体相互作用蛋白激酶1（RIPK1）、RIPK3和磷酸化混合谱系激酶样蛋白（p-MLKL）。在HTR8/SVneo细胞中检测缺氧对滋养细胞坏死性凋亡的影响。通过转染沉默或过表达SIRT3的小干扰RNA慢病毒，研究SIRT3对HTR8/SVneo细胞坏死性凋亡、侵袭、迁移及成管能力的影响。
与健康妊娠对照组相比，子痫前期患者胎盘滋养细胞中SIRT3表达降低，RIPK1、RIPK3和p-MLKL表达升高。缺氧增加了HTR8/SVneo细胞中RIPK1、RIPK3和p-MLKL的表达，而坏死性凋亡抑制剂-1预处理降低了缺氧条件下HTR8/SVneo细胞中RIPK1、RIPK3和p-MLKL的表达。沉默SIRT3增加了缺氧条件下HTR8/SVneo细胞中RIPK1、RIPK3和p-MLKL的表达，并抑制了其侵袭、迁移及成管能力。过表达SIRT3则产生相反的结果。
我们报道SIRT3缺乏可能通过增加坏死性凋亡和导致滋养细胞生物学行为异常参与子痫前期的发病机制。其潜在机制需要进一步研究。
