Li Ping, Xiang Yixiao, Wei Jinzhi, Xu Xingyan, Wang Jiale, Yu Haowei, Li Xiaosa, Lin Huiping, Fu Xiaodong
The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511518, Guangdong, People's Republic of China.
Key Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, People's Republic of China.
Cell Mol Biol Lett. 2025 Apr 4;30(1):41. doi: 10.1186/s11658-025-00720-y.
The incidence of atherosclerosis markedly rises following menopause. Our previous findings demonstrated that elevated follicle-stimulating hormone (FSH) levels in postmenopausal women accelerate atherosclerosis progression. Plaque instability, the fundamental pathological factor in acute coronary syndrome, primarily results from vascular embolism due to plaque rupture. Recent evidence highlights that endothelial-to-mesenchymal transition (EndMT) exacerbates plaque instability, although the link between FSH and EndMT has not been fully established. This investigation sought to explore the possible influence of FSH in modulating EndMT.
In this study, apolipoprotein E-deficient (ApoE) mice served as an atherosclerosis model, while human umbilical vascular endothelial cells (HUVECs) were used as cellular models. Protein levels were assessed through immunochemical techniques, gene expression was quantified via RT-qPCR, and nucleic acid-protein interactions were evaluated using immunoprecipitation. The m6A modification status was determined by MeRIP, and cellular behaviors were analyzed through standard biochemical assays.
Our results indicate that FSH induces EndMT both in vitro and in vivo. Additional investigation suggested that FSH upregulates the transcription factor Forkhead box protein M1 (FOXM1) at both protein and mRNA levels by enhancing the expression of AlkB homolog 5, RNA demethylase (ALKBH5). FSH reduces m6A modifications on FOXM1 through ALKBH5, leading to increased nascent transcript levels and mRNA stability of FOXM1. Dual-luciferase reporter assays highlighted cAMP-response element binding protein (CREB)'s essential function in facilitating the FSH-induced upregulation of ALKBH5.
These findings suggest that FSH promotes ALKBH5 expression, facilitates N-methyladenosine (m6A) demethylation on FOXM1, and consequently, induces EndMT. This study elucidates the impact of FSH on plaque instability and provides insights into potential strategies to prevent acute coronary syndrome in postmenopausal women.
绝经后动脉粥样硬化的发病率显著上升。我们之前的研究结果表明，绝经后女性中升高的促卵泡生成素（FSH）水平会加速动脉粥样硬化的进展。斑块不稳定是急性冠状动脉综合征的基本病理因素，主要由斑块破裂导致的血管栓塞引起。最近的证据表明，内皮-间充质转化（EndMT）会加剧斑块不稳定，尽管FSH与EndMT之间的联系尚未完全确立。本研究旨在探讨FSH在调节EndMT方面的可能影响。
在本研究中，载脂蛋白E缺陷（ApoE）小鼠作为动脉粥样硬化模型，而人脐静脉血管内皮细胞（HUVECs）用作细胞模型。通过免疫化学技术评估蛋白质水平，通过RT-qPCR定量基因表达，并使用免疫沉淀评估核酸-蛋白质相互作用。通过MeRIP确定m6A修饰状态，并通过标准生化分析来分析细胞行为。
我们的结果表明，FSH在体外和体内均诱导EndMT。进一步的研究表明，FSH通过增强RNA去甲基化酶AlkB同源物5（ALKBH5）的表达，在蛋白质和mRNA水平上上调转录因子叉头框蛋白M1（FOXM1）。FSH通过ALKBH5降低FOXM1上的m6A修饰，导致FOXM1的新生转录本水平和mRNA稳定性增加。双荧光素酶报告基因分析突出了环磷酸腺苷反应元件结合蛋白（CREB）在促进FSH诱导的ALKBH5上调中的重要作用。
这些发现表明，FSH促进ALKBH5表达，促进FOXM1上的N-甲基腺苷（m6A）去甲基化，从而诱导EndMT。本研究阐明了FSH对斑块不稳定的影响，并为预防绝经后女性急性冠状动脉综合征的潜在策略提供了见解。
