Lactate promotes premature aging of preeclampsia placentas through histone lactylation-regulated GADD45A

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta Pub Date : 2025-01-24 DOI:10.1016/j.placenta.2025.01.010

Xiang Li , Qianghua Wang , Jiaojiao Fei , Zhixin Jin , Yue Wu , Yafen Tao , Chuanyue Jiang , Xuegu Wang , Nana Yang , Biao Ding , Chengli Dou

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引用次数: 0

Abstract

Background

Premature placental aging has been linked to preeclampsia (PE), with lactate identified as a promoter of cellular senescence in various cell types. In this study, we explored the role and underlying mechanisms of lactate in driving premature placental aging associated with PE.

Methods

To evaluate senescence markers in placental samples or trophoblast cells, we conducted SA-β-Gal staining, western blotting, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence assays. SiRNA transfection was used to reduce GADD45A expression in HTR-8/SVneo cells exposed to lactate. Additionally, chromatin immunoprecipitation-qPCR (ChIP-qPCR) was used to analyze histone lactylation at the GADD45A promoter region.

Results

SA-β-Gal staining indicated a significant increase in senescent cell proportions in placentas from PE patients compared to controls. Treatment with lactate enhanced senescence in trophoblast cells, leading to an increase in P16 expression. RNA sequencing analysis showed that genes differentially expressed in lactate-treated cells were involved in pathways linked to cellular senescence. Additionally, lactate augmented GADD45A expression and increased histone lactylation at its promoter region, while knocking down GADD45A in trophoblast cells mitigated the senescence induced by lactate.

Conclusions

Lactate promotes trophoblast senescence through epigenetic upregulation of GADD45A expression, offering fresh perspectives on the molecular mechanisms and potential treatment targets for PE.

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来源期刊

Placenta 医学-发育生物学

CiteScore

6.30

自引率

10.50%

发文量

391

审稿时长

78 days

期刊介绍： Placenta publishes high-quality original articles and invited topical reviews on all aspects of human and animal placentation, and the interactions between the mother, the placenta and fetal development. Topics covered include evolution, development, genetics and epigenetics, stem cells, metabolism, transport, immunology, pathology, pharmacology, cell and molecular biology, and developmental programming. The Editors welcome studies on implantation and the endometrium, comparative placentation, the uterine and umbilical circulations, the relationship between fetal and placental development, clinical aspects of altered placental development or function, the placental membranes, the influence of paternal factors on placental development or function, and the assessment of biomarkers of placental disorders.

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