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

  • Placenta. 2024 Oct 22:158:145-155. doi: 10.1016/j.placenta.2024.10.013.
Xiaojing Yue  1 ,  Menglan Pang  1 ,  Yun Chen  1 ,  Zhixing Cheng  1 ,  Ruisi Zhou  1 ,  Yu Wang  1 ,  Zhiqiang Zha  1 ,  Liping Huang  2
Affiliations
  • 1. Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
  • 2. Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. Electronic address: [email protected].
PMID: 39490110 DOI: 10.1016/j.placenta.2024.10.013
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.

Keywords
CREB; Ferroptosis; HO-1; Preeclampsia; Puerarin.
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