Puerarin alleviates symptoms of preeclampsia through the repression of trophoblast ferroptosis via the CREB/HO-1 pathway

IF 3 2区 医学 Q2 DEVELOPMENTAL BIOLOGY
Xiaojing Yue , Menglan Pang , Yun Chen, Zhixing Cheng, Ruisi Zhou, Yu Wang, Zhiqiang Zha, Liping Huang
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Abstract

Introduction

Preeclampsia (PE) is a pregnancy-associated complication characterised by new-onset hypertension and proteinuria. This study explored the therapeutic potential of puerarin (Pue) in PE and investigated the underlying mechanism, with a focus on placental ferroptosis.

Methods

Using an NG-nitro-L-arginine methyl ester (L-NAME)-induced PE mouse model, we assessed the effects of Pue on PE phenotypes and placental ferroptosis. Antioxidative and anti-ferroptotic effects of Pue were studied in three ferroptotic cell models (hypoxia/reperfusion, cobalt chloride, and erastin). The regulation of Pue on cAMP response element binding protein (CREB) and heme oxygenase-1 (HO-1) was evaluated through gain- and loss-of-function assays. Luciferase assays were used to elucidate the effect of Flag-CREB on Hmox1 promoter fragments. CREB/HO-1 modulation by Pue was validated in mouse placentas with PE.

Results

Pue significantly alleviated maternal hypertension, proteinuria, fetal growth restriction, and placental damage in PE mice. This was associated with an upregulation of the anti-ferroptosis system (glutathione peroxidase 4 [GPX4], cys2/glutamate antiporter [SLC7A11], and glutathione [GSH]) and repression of reactive oxygen species (ROS) and malondialdehyde (MDA) in trophoblasts. Pue reduced HO-1 and CREB, and HO-1 deficiency upregulated GPX4 and SLC7A11. Manipulation of CREB expression led to changes in HO-1/GPX4; whereas, the regulation reversed by Pue administration. Flag-CREB enhanced luciferase activity on the full length Hmox1 promoter (−2000/+78), which contains three CREB1 binding sites (S1–S3). In contrast, no increase in luciferase activity was observed with promoter fragments (−850/+78) and (−550/+78), which contain only the CREB1 binding sites S2 and S3, respectively.

Discussion

Pue ameliorated PE-like symptoms in mice by repressing trophoblast ferroptosis via inhibition of CREB signalling and affecting the Homx1 promoter.
葛根素通过CREB/HO-1途径抑制滋养细胞铁凋亡,从而缓解子痫前期症状
导言子痫前期(PE)是一种与妊娠相关的并发症,以新发高血压和蛋白尿为特征。本研究探讨了葛根素(Pue)在子痫中的治疗潜力,并研究了其潜在机制,重点是胎盘铁绒毛膜变性。在三种铁变态反应细胞模型(缺氧/再灌注、氯化钴和麦拉宁)中研究了Pue的抗氧化和抗铁变态反应作用。通过功能增益和功能缺失试验评估了 Pue 对 cAMP 反应元件结合蛋白(CREB)和血红素加氧酶-1(HO-1)的调节作用。荧光素酶试验用于阐明 Flag-CREB 对 Hmox1 启动子片段的影响。结果 Pue 能显著缓解 PE 小鼠的母体高血压、蛋白尿、胎儿生长受限和胎盘损伤。这与上调滋养细胞中的抗铁锈色素沉着系统(谷胱甘肽过氧化物酶 4 [GPX4]、cys2/谷氨酸转运体 [SLC7A11] 和谷胱甘肽 [GSH])以及抑制活性氧(ROS)和丙二醛(MDA)有关。Pue会降低HO-1和CREB,而HO-1的缺乏会上调GPX4和SLC7A11。操纵 CREB 的表达会导致 HO-1/GPX4 的变化;而服用 Pue 则会逆转这种调节。Flag-CREB 增强了全长 Hmox1 启动子(-2000/+78)上的荧光素酶活性,该启动子包含三个 CREB1 结合位点(S1-S3)。与此相反,启动子片段(-850/+78)和(-550/+78)的荧光素酶活性没有增加,这两个片段分别只包含 CREB1 结合位点 S2 和 S3。
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来源期刊
Placenta
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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