妊娠期糖尿病胎盘滋养细胞铁死亡超微结构及铁死亡相关基因ACSL4、GPX4的表达
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常州市妇幼保健院,常州医学中心,南京医科大学

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常州市科技局应用基础项目(编号:CJ20220117、CJ20220259)


Ultrastructure of ferroptosis and expression of ferroptosis-related ACSL4 and GPX4 genes in placental trophoblasts of gestational diabetes mellitus
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Changzhou maternal and Child Health Care Hospital,Changzhou Medical Center,Nanjing Medical University

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    摘要:

    目的:观察妊娠期糖尿病(gestational diabetes mellitus,GDM)胎盘滋养细胞铁死亡超微结构,探讨铁死亡在GDM发生发展中的作用。方法:选取2020年9月至2022年12月在常州妇幼保健院分娩的孕妇,孕24-28周行OGTT。将确诊GDM的孕妇作为研究对象,根据干预情况,分为通过饮食治疗控制血糖满意的孕妇(G1组)、口服二甲双胍控制血糖的GDM孕妇(G2组)、需胰岛素控制血糖的GDM孕妇(G3组)、血糖控制不满意但拒用药的GDM孕妇(G4组)各30例,正常孕妇(N组)为对照组。通过透射电镜观察各组胎盘滋养细胞超微结构,普鲁士蓝染色检查胎盘铁沉积情况,免疫组化检测胎盘长链脂酰辅酶A合成酶4(Acyl-CoA synthetase long chain family member 4,ACSL4)、谷胱甘肽过氧化物酶4(glutathione peroxidase 4,GPX4)在合体滋养细胞层的定位和表达;Western blot检测胎盘ACSL4、GPX4蛋白表达;qRT-PCR检测胎盘ACSL4、GPX4mRNA转录水平。结果:透视电镜下四组GDM胎盘均可见不同程度的线粒体形态学改变,G1、G2、G3组线粒体改变较轻,G4组见典型的铁死亡萎缩线粒体。普鲁士蓝染色显示五组胎盘均见含铁颗粒,四组GDM组胎盘中含铁颗粒较N组明显增多,G1、G2、G3组胎盘中的含铁颗粒较G4组明显减少。ACSL4、GPX4主要在合体滋养细胞的胞质中表达,与N组相比,四组GDM孕妇胎盘中ACSL4蛋白表达增加,GPX4蛋白表达下降,ACSL4、GPX4 mRNA转录水平无显著性差异。结论:妊娠期糖尿病患者胎盘滋养细胞中存在铁死亡,且与病情严重程度和用药相关。GDM患者胎盘铁死亡与ACSL4、GPX4异常表达相关,二甲双胍和胰岛素有改善胎盘滋养细胞铁死亡的作用。

    Abstract:

    Objective:This study aims to observe the ultrastructure of ferroptosis in placental trophoblast cells of gestational diabetes mellitus (GDM), and investigate the role of ferroptosis in the occurrence and development of GDM.Methods:Pregnant women who delivered in Changzhou Maternal and Child Health Hospital from September 2020 to December 2022 were selected . Oral glucose tolerance tests were performed during 24-28 weeks of pregnancy.Pregnant women diagnosed with GDM were categorized based on interventions:GDM women controlled by diet therapy (G1 group), those controlled by oral metformin (G2 group), those requiring insulin for blood glucose control (G3 group), and those with unsatisfactory blood glucose control refusing medication (G4 group), each comprising 30 cases. Normal pregnant women (N group) served as the control. The ultrastructure of placental trophoblast cells was observed using transmission electron microscopy.The placental iron deposition was detected by Prussian blue staining.The localizations and expressions of Acyl-CoA synthetase long chain family member 4(ACSL4) and glutathione peroxidase 4(GPX4) in the syncytiotrophoblast layer were detected by immunohistochemistry.The protein expressions and the mRNA transcription levels of ACSL4 and GPX4 in placental tissues were detected by Western blotting and qRT-PCR,respectively.Results:Transmission electron microscopy revealed varying degrees of mitochondrial morphological changes in all four GDM placental groups.G1, G2, and G3 groups showed milder mitochondrial changes, while the G4 group exhibited typical ferroptosis with shrunken mitochondria.Prussian blue staining demonstrated iron particles in all five groups, with a significant increase in iron particles in the GDM placental groups compared to the N group. The iron particles in the G1,G2 and G3 groups were fewer than the G4 group.ACSL4 and GPX4 were predominantly expressed in the cytoplasm of syncytiotrophoblast cells.Compared to the N group, GDM placental tissues in all four groups showed increased ACSL4 protein expression and decreased GPX4 protein expression, with no significant differences in ACSL4 and GPX4 mRNA transcription levels.Conclusion:Ferroptosis exists in placental trophoblast cells of GDM patients, and it is correlated with the severity of the disease and medication.Placental ferroptosis in GDM patients is associated with abnormal expression of ACSL4 and GPX4.Metformin and insulin have a role in improving ferroptosis of placental trophoblast cells.

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  • 收稿日期:2023-06-14
  • 最后修改日期:2023-11-30
  • 录用日期:2024-01-09
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