炎症诱导的 PFKFB3 介导的糖酵解通过 PI3K-Akt-mTOR 途径促进早产小鼠子宫肌收缩

Inflammation-induced PFKFB3-mediated glycolysis promoting myometrium contraction through the PI3K-Akt-mTOR pathway in preterm birth mice

炎症诱导的 PFKFB3 介导的糖酵解通过 PI3K-Akt-mTOR 途径促进早产小鼠子宫肌收缩

Authors: Jing He, Xuan Li, Huihui Yu, Chenyi Xu, Ruixian Tian, Ping Zhou, Zongzhi Yin

Source: American Journal of Physiology-cell Physiology

DOI: 10.1152/ajpcell.00704.2024

 

Abstract

Inflammation is a significant risk factor for preterm birth. Inflammation enhances glycolytic processes in various cell types and contributes to the development of myometrial contractions. However, the potential of inflammation to activate glycolysis in pregnant murine uterine smooth muscle cells (mUSMCs) and its role in promoting inflammatory preterm birth remain unexplored. In this study, lipopolysaccharide was employed to establish both cell and animal inflammation models. We found that inflammation of mUSMCs during late pregnancy could initiate glycolysis and promote cell contraction. Subsequently, the inhibition of glycolysis using the glycolysis inhibitor 2-deoxyglucose can reverse inflammation-induced cell contraction. The expression of 6-phosphofructokinase 2 kinase (PFKFB3) was significantly upregulated in mUSMCs following lipopolysaccharide stimulation. In addition, lactate accumulation and enhanced contraction were observed. Inhibition of PFKFB3 reversed the lactate accumulation and enhanced contraction induced by inflammation. We also found that inflammation activated the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of the rapamycin (mTOR) pathway, leading to the upregulation of PFKFB3 expression. The PI3K-Akt pathway inhibitor LY294002 and the mTOR pathway inhibitor rapamycin effectively inhibited the upregulation of PFKFB3 protein expression, lactate production, and the enhancement of cell contraction induced by lipopolysaccharide. This study indicates that inflammation regulates PFKFB3 through the PI3K-Akt-mTOR pathway, which enhances the glycolytic process in pregnant mUSMCs, ultimately leading to myometrial contraction.

NEW & NOTEWORTHY: Expression of PFKFB3, a key enzyme in glycolysis, was significantly upregulated both in the mUSMCs and myometrium of mice during late pregnancy after lipopolysaccharide stimulation. Activation of the PI3K-Akt-mTOR pathway enhanced PFKFB3 expression, which is involved in the initiation of glycolysis. Inflammation-activated PFKFB3 via the PI3K-Akt-mTOR pathway, which enhances the cellular glycolytic process and thus promotes myometrium contraction in pregnancy.

Keywords: PI3K-Akt-mTOR; glycolysis; inflammation; myometrium contraction; preterm birth.

摘要

炎症是早产的一个重要风险因素。炎症会增强各种细胞类型的糖酵解过程，并促进子宫肌收缩的发展。然而，炎症激活妊娠小鼠子宫平滑肌细胞（mUSMCs）糖酵解的潜力及其在促进炎症性早产中的作用仍未得到研究。本研究利用脂多糖建立了细胞和动物炎症模型。我们发现，妊娠晚期mUSMCs的炎症可启动糖酵解并促进细胞收缩。随后，使用糖酵解抑制剂 2-脱氧葡萄糖抑制糖酵解可逆转炎症诱导的细胞收缩。脂多糖刺激 mUSMCs 后，6-磷酸果糖激酶 2 激酶（PFKFB3）的表达明显上调。此外，还观察到乳酸积累和收缩增强。抑制 PFKFB3 可逆转炎症引起的乳酸积累和收缩增强。我们还发现，炎症激活了磷脂酰肌醇 3-激酶（PI3K）-蛋白激酶 B（Akt）-雷帕霉素哺乳动物靶标（mTOR）通路，导致 PFKFB3 表达上调。PI3K-Akt通路抑制剂LY294002和mTOR通路抑制剂雷帕霉素能有效抑制脂多糖诱导的PFKFB3蛋白表达上调、乳酸生成和细胞收缩增强。这项研究表明，炎症通过PI3K-Akt-mTOR途径调控PFKFB3，从而增强妊娠母细胞的糖酵解过程，最终导致子宫收缩。PI3K-Akt-mTOR 通路的激活增强了 PFKFB3 的表达，而 PFKFB3 参与糖酵解的启动。炎症通过PI3K-Akt-mTOR途径激活了PFKFB3，增强了细胞糖酵解过程，从而促进了妊娠期子宫收缩。

关键词：PI3K-Akt-mTOR；糖酵解；炎症；子宫收缩；早产