Role and mechanism of endoplasmic reticulum stress in regulating the apoptosis of hypoxia induced preeclampsia trophoblasts
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摘要: 目的 研究内质网应激（ERS）在体外缺氧诱导子痫前期（PE）滋养细胞模型中调控凋亡的作用及机制。方法 收集PE胎盘和健康胎盘，检测细胞凋亡率及ERS标志基因：葡萄糖调节蛋白78（GRP78）、ERS凋亡基因C/EBP同源蛋白（CHOP）、磷酸化JNK（p-JNK）、含半胱氨酸的天冬氨酸蛋白水解酶-12（Cleaved caspase-12）的表达水平。培养胎盘滋养细胞HTR8/SVneo，采用低氧（1% O2）处理24 h诱导PE细胞模型，采用ERS激动剂处理细胞，在PE细胞模型诱导过程中转染CHOP siRNA或给予JNK拮抗剂、Caspase-12抑制剂，检测细胞增殖水平（D值）、凋亡率及GRP78、CHOP、p-JNK、Cleaved caspase-12的表达水平。结果 PE胎盘细胞凋亡率及GRP78、CHOP、p-JNK、Cleaved caspase-12的表达水平高于健康胎盘（P<0.05），且细胞凋亡率与GRP78、CHOP、p-JNK、Cleaved caspase-12的表达水平呈正相关；PE组及ERS激动剂组细胞的D值低于对照组，凋亡率及GRP78、CHOP、p-JNK、Cleaved caspase-12的表达水平高于对照组（P<0.05）；缺氧诱导PE模型过程中转染CHOP siRNA降低CHOP表达，给予JNK拮抗剂降低p-JNK表达，给予Caspase-12抑制剂降低Cleaved caspase-12表达后，细胞D值升高，凋亡率及GRP78的表达水平降低（P<0.05）。结论 缺氧诱导PE滋养细胞模型中ERS，通过CHOP、JNK和Caspase-12介导细胞凋亡。Abstract: Objective To study the role and mechanism of endoplasmic reticulum stress (ERS) in regulating the apoptosis of hypoxia-induced preeclampsia (PE) trophoblasts in vitro.Methods PE placenta and healthy placenta were collected, and then the apoptosis rate and the levels of ERS marker gene glucose regulated protein 78 (GRP78), ERS apoptosis gene C/EBP homologous protein (CHOP), phosphorylated JNK (p-JNK) and Cleaved caspase-12 were examined. The placental trophoblasts HTR8/SVneo were cultured. A PE cell model was induced by exposing to low oxygen (1% O2) for 24 h. The cells were treated with ERS agonists. During the induction of the PE cell model,the cells were transfected with CHOP siRNA or treated with JNK inhibitor and Caspase-12 inhibitor. Cell proliferation (D value), apoptosis rate and the levels of GRP78, CHOP, p-JNK and Cleaved caspase-12 were measured.Results The apoptosis rate and the levels of GRP78, CHOP, p-JNK and Cleaved caspase-12 in PE placenta were higher than those in healthy placenta (P<0.05). Cell apoptosis rate was positively correlated with the levels of GRP78, CHOP, p-JNK, and Cleaved caspase-12. The D value of cells in the PE group and ERS agonist group were lower than those in the control group, and the apoptosis rate and the the levels of GRP78, CHOP, p-JNK and Cleaved caspase-12 were higher than those in the control group (P<0.05). Transfection of CHOP siRNA reduced CHOP expression, JNK inhibitor reduced p-JNK expression, and Caspase-12 inhibitor reduced Cleaved caspase-12 expression in the hypoxia-induced PE model, leading to increased D value, reduced apoptosis rate, and lowered GRP78 expression (P<0.05).Conclusions ERS mediates cell apoptosis through CHOP, JNK, and Caspase-12 in the hypoxia-induced PE trophoblast model.
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Keywords:
- preeclampsia /
- endoplasmic reticulum stress /
- placenta /
- trophoblast /
- apoptosis
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[1] Ren ZL,Gao YF,Gao Y,et al.Distinct placental molecular processes associated with early-onset and late-onset preeclampsia[J].Theranostics,2021,11(10):5028-5044.
[2] 李莉,郑丹,张佳,等.内质网应激因子Caspase-12与子痫前期发病机制的关系[J].江西医药,2021,56(4):533-536. [3] Zhao JW,Chow RP,McLeese RH,et al.Modelling preeclampsia:a comparative analysis of the common human trophoblast cell lines[J].FASEB Bioadv,2021,3(1):23-35.
[4] 杨晓涛,韩顶立,Philip N.Baker,等.体外缺氧诱导子痫前期滋养细胞模型优化及代谢组学鉴定[J].重庆医科大学学报,2017,42(8):1045-1052. [5] Vangrieken P,Al-Nasiry S,Bast A,et al.Hypoxia-induced mitochondrial abnormalities in cells of the placenta[J/OL].PLoS One,2021,16(1):e0245155.
[6] Huang CY,Deng JS,Huang WC,et al.Attenuation of lipopolysaccharide-induced acute lung injury by hispolon in mice,through regulating the TLR4/PI3K/Akt/mTOR and Keap1/Nrf2/HO-1 pathways,and suppressing oxidative stress-mediated ER stress-induced apoptosis and autophagy[J].Nutrients,2020,12(6):1742.
[7] Song SL,Tan J,Miao YY,et al.Intermittent-hypoxia-induced autophagy activation through the ER-stress-related PERK/eIF2α/ATF4 pathway is a protective response to pancreatic β-cell apoptosis[J].Cell Physiol Biochem,2018,51(6):2955-2971.
[8] Hou XL,Li LJ,Chen S,et al.MKP-1 overexpression reduces postischemic myocardial damage through attenuation of ER stress and mitochondrial damage[J/OL].Oxid Med Cell Longev,2021,2021:8905578.
[9] Du L,He F,Kuang L,et al.eNOS/iNOS and endoplasmic reticulum stress-induced apoptosis in the placentas of patients with preeclampsia[J].J Hum Hypertens,2017,31(1):49-55.
[10] Bastida-Ruiz D,Aguilar E,Ditisheim A,et al.Endoplasmic reticulum stress responses in placentation-A true balancing act[J].Placenta,2017,57:163-169.
[11] Wu MZ,Fu T,Chen JX,et al.LncRNA GOLGA2P10 is induced by PERK/ATF4/CHOP signaling and protects tumor cells from ER stress-induced apoptosis by regulating Bcl-2 family members[J].Cell Death Dis,2020,11(4):276.
[12] Wang XT,Cui XP,Zhu CW,et al.FKBP11 protects intestinal epithelial cells against inflammation-induced apoptosis via the JNK-caspase pathway in Crohn's disease[J].Mol Med Rep,2018,18(5):4428-4438.
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