The Study Of SIRT3 In The Pathogenesis Of Preeclampsia By Regulating The Biological Function Of Trophoblast Cells

Background:Silence information regulator 3(SIRT3)is a kind of nicotinamide adenine dinucleotide(NAD+)dependent histone deacetylase.SIRT3 can deacetylate numerous mitochondrial enzymes.Increasing evidence shows a role for SIRT3 in regulating mitochondrial morphology and function,energy metabolism,reactive oxygen species(ROS)detoxification,intracellular signaling transmission,cell invasion and migration.However,the role of SIRT3 in the preeclampsia pathogenesis remains to be elucidated.Objective: To detect SIRT3 expression and localization in human placenta during normal pregnancy and preeclampsia.To study the effects of SIRT3 on the function of trophoblast cell line HTR-8/SVneo cells.By constructing a model of oxidative stress in trophoblasts,we explored the possible mechanism of SIRT3 in PE to improve oxidative stress.Methods: Immunohistochemistry assays and western blotting were used to detect the localization and expression of SIRT3 protein in the placentae at different stages of pregnancy and early and late onset preeclampsia.Transiently transfected the plasmid was used to make HTR8/Svneo cells overexpress SIRT3.Then we detect the effects of SIRT3 on cell proliferation,cell cycle,invasion and migration of HTR-8/SVneo cells.In addition,the model of oxidative stress in trophoblasts was constructed through Co Cl2 to study the regulation of SIRT3 on the ability of HTR-8/Svneo cells to resist oxidative stress.At last we used western blotting to observe several key proteins on the AKT signaling pathway and explore the molecular mechanism of SIRT3 participating in the preeclampsia.Results: SIRT3 was expressed in human placental tissues at different stages of pregnancy,and was mainly localized within the cytotrophoblasts,syncytiotrophoblast and interstitial extravillous trophoblasts.During the whole pregnancy,the expression level of SIRT3 in placental tissues was lowest in the third trimester.Moreover,the expression of SIRT3 in placenta of early and late onset preeclampsia was significantly lower than that in the corresponding normal control group.The up-regulated expression of SIRT3 can enhance the proliferative ability of HTR-8/SVneo cells,block trophoblast cells in cell stage G1,and convert them to an invasive phenotype.In addition,increased SIRT3 expression in HTR-8/SVneo cells significantly alleviated oxidative stress induced by Co Cl2 in trophoblast cells.Moreover,SIRT3 overexpression also significantly upregulated the expression of key proteins in the Akt signaling pathway.Conclusion: This study demonstrated the expression profile of SIRT3 in normal and preeclampsia placental tissue and its effect on trophoblast function.Studies have found that SIRT3 can enhance the proliferation,migration and invasion of HTR-8/SVneo cells,and can also significantly alleviate the oxidative stress of trophoblast cells induced by Co Cl2.These findings suggest that SIRT3 play an important role in regulating uterine spiral artery recasting and placental oxidative stress through the AKT signaling pathway.The results provided new insights into finding the drug treatment targets and etiology of preeclampsia.