Simvastatin ameliorates adverse pregnancy by inhibiting glycolysis-related NETs in obstetrical antiphospholipid syndrome

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2024-11-04 DOI:10.1016/j.lfs.2024.123215

Ruiheng Huo , Qipeng Sun , Qingfeng Lv , Yuan Wang , Weiyi Qi , Meihua Zhang , Lei Li , Xietong Wang

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引用次数: 0

Abstract

Aims

Some patients with Obstetric Antiphospholipid Syndrome (OAPS) still experience miscarriage and placental dysfunction after routine treatment, which is related to an abnormal increase in neutrophil extracellular traps (NETs). The labeling of statins has been revised to remove the contraindication for use during pregnancy. Our aim is to investigate the effect of Simvastatin on pregnancy outcomes in OAPS and its correlation mechanisms with NETs.

Main methods

The effect of Simvastatin on pregnancy outcomes was observed. The effect of simvastatin on the function and apoptosis of neutrophils has evaluated. The effect of Simvastatin to NETs and the changes in oxidative stress levels were observed. Different groups of NETs were extracted to intervene the HTR8-Svneo.RNA-seq analysis of the mechanism of which Simvastatin reduces NETs. Seahorse experiment detected the effect of Simvastatin on neutrophil glycolysis levels. Fluorescence co-localization and flow cytometry and Co-IP were used to verify relevant mechanisms.

Key findings

In the OAPS mice, Simvastatin can reduce embryo absorption rate, reshape placental blood flow perfusion. Simultaneously reducing the production of NETs both in vivo and vitro, remolding oxidative stress. Simvastatin can improve neutrophil dysfunction caused by aPL-IgG. The reduction of NETs improved HTR8-Svneo's dysfunction. The intervention of Simvastatin on neutrophils under the stimulation of aPL-IgG showed a signature in glycolytic. The key rate limiting enzyme PKM2 in glycolysis interacts with Cit-H2b and PI3K/AKT signaling pathway.

Significance

Our study providing basic theoretical support for the treatment of OAPS with Simvastatin.

Abstract Image

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辛伐他汀通过抑制产科抗磷脂综合征中与糖酵解相关的NET，改善不良妊娠。

目的：一些产科抗磷脂综合征（OAPS）患者在接受常规治疗后仍会出现流产和胎盘功能障碍，这与中性粒细胞胞外捕获物（NET）异常增加有关。他汀类药物的标签已被修订，取消了妊娠期禁用的规定。我们的目的是研究辛伐他汀对 OAPS 妊娠结局的影响及其与 NETs 的相关机制：主要方法：观察辛伐他汀对妊娠结局的影响。评估辛伐他汀对中性粒细胞功能和凋亡的影响。观察辛伐他汀对NET的影响以及氧化应激水平的变化。提取不同组别的NETs，干预HTR8-Svneo.RNA-seq分析辛伐他汀减少NETs的机制。海马实验检测了辛伐他汀对中性粒细胞糖酵解水平的影响。利用荧光共定位、流式细胞术和Co-IP验证了相关机制：主要发现：辛伐他汀可降低胚胎吸收率，重塑胎盘血流灌注，同时减少中性粒细胞糖酵解的产生。同时减少体内和体外NET的产生，重塑氧化应激。辛伐他汀能改善 aPL-IgG 引起的中性粒细胞功能障碍。NET的减少改善了HTR8-Svneo的功能障碍。在 aPL-IgG 的刺激下，辛伐他汀对中性粒细胞的干预显示出糖酵解的特征。糖酵解过程中的关键限速酶PKM2与Cit-H2b和PI3K/AKT信号通路相互作用：我们的研究为辛伐他汀治疗 OAPS 提供了基础理论支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.