Hyperlipidemia Triggers Trophoblast Cell Dysfunction and Preeclampsia via the AMPK/GATA3/FTL Pathway.

IF 6.9 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Hanhui Nie,Xiufang Wang,Lei Guo,Jiachun Wei,Yiling Wei,Yudie Gao,Jian Wang,Ka Cheuk Yip,Xiaman Huang,Qiao Zhang,Feng Gao,Ruiman Li
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Abstract

BACKGROUND Preeclampsia, a severe pregnancy complication with an incompletely deciphered cause, is strongly associated with hyperlipidemia. Our previous studies demonstrated that FTL (ferritin light chain) expression was diminished in preeclampsia placentas and that FTL downregulation inhibited trophoblast invasiveness and migration while promoting apoptosis, contributing to preeclampsia development. However, the potential interplay between hyperlipidemia and FTL in the pathogenesis of preeclampsia, as well as the regulatory mechanism involved, remains to be elucidated. METHODS We conducted Spearman correlation analysis, used a high-fat diet-fed mice model, cell culture, and molecular biology assays, including immunohistochemistry, chromatin immunoprecipitation, and dual-luciferase reporter gene assays, to explore the impact of hyperlipidemia on the development of preeclampsia and to elucidate the molecular mechanisms involved. RESULTS Pregnant women with preeclampsia presented elevated serum total cholesterol, triglycerides, and low-density lipoprotein, with reduced high-density lipoprotein. Similarly, high-fat diet-fed mice exhibited dyslipidemia and preeclampsia-like characteristics. FTL expression was reduced in the placentas of patients with preeclampsia and high-fat diet-fed pregnant mice. In vitro, palmitic acid treatment reduced FTL expression, increased oxidative stress, and impaired trophoblast migration and invasion. GATA3 (GATA binding protein 3) was predicted to be an upstream transcription factor for FTL, with its knockdown reducing and its overexpression increasing FTL levels. Further analysis indicated that palmitic acid suppressed FTL expression by inhibiting GATA3 nuclear translocation and that AMPK (AMP-activated protein kinase) activation rescued FTL expression and restored trophoblast function. CONCLUSIONS This study revealed that high lipid levels contribute to preeclampsia by downregulating FTL through the AMPK-GATA3 pathway, highlighting potential therapeutic targets for preeclampsia management.
高脂血症通过AMPK/GATA3/FTL通路触发滋养细胞功能障碍和子痫前期
背景:子痫前期是一种严重的妊娠并发症,其病因尚未完全明确,与高脂血症密切相关。我们之前的研究表明,FTL(铁蛋白轻链)在子痫前期胎盘中表达降低,FTL下调抑制滋养细胞侵袭和迁移,同时促进细胞凋亡,促进子痫前期的发展。然而,高脂血症和FTL在子痫前期发病中的潜在相互作用及其调控机制仍有待阐明。方法采用Spearman相关分析、高脂饮食小鼠模型、细胞培养、免疫组化、染色质免疫沉淀、双荧光素酶报告基因检测等分子生物学方法,探讨高脂血症对子痫前期发生的影响,并阐明其分子机制。结果子痫前期孕妇血清总胆固醇、甘油三酯、低密度脂蛋白升高,高密度脂蛋白降低。同样,高脂肪饮食喂养的小鼠表现出血脂异常和子痫前期样特征。FTL在子痫前期患者和高脂肪饮食喂养的妊娠小鼠的胎盘中表达减少。在体外,棕榈酸处理降低了FTL的表达,增加了氧化应激,损害了滋养细胞的迁移和侵袭。GATA3 (GATA结合蛋白3)被预测为FTL的上游转录因子,其敲低减少,过表达增加FTL水平。进一步分析表明,棕榈酸通过抑制GATA3核易位抑制FTL的表达,AMPK (amp活化蛋白激酶)的激活挽救了FTL的表达,恢复了滋养细胞的功能。结论本研究揭示了高脂水平通过AMPK-GATA3通路下调FTL参与子痫前期,提示了子痫前期治疗的潜在靶点。
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来源期刊
Hypertension
Hypertension 医学-外周血管病
CiteScore
15.90
自引率
4.80%
发文量
1006
审稿时长
1 months
期刊介绍: Hypertension presents top-tier articles on high blood pressure in each monthly release. These articles delve into basic science, clinical treatment, and prevention of hypertension and associated cardiovascular, metabolic, and renal conditions. Renowned for their lasting significance, these papers contribute to advancing our understanding and management of hypertension-related issues.
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