FSH调控miR-7641/Twist1诱导内皮间充质转化及动脉粥样斑块不稳定性

The incidence rate of atherosclerosis sharply increases after menopause, while the detailed mechanisms remain obscure. Recently we have reported that high level of follicle stimulating hormone (FSH) in postmenopausal women accelerated the development of atherosclerosis. Plaque instability is the critical pathological basis for clinical acute coronary syndrome. The latest evidence indicates that endothelial to mesenchymal transition (EndMT) increases plaque instability. The preliminary results of this project showed that FSH induced EndMT. FSH also downregulated miR-7641 expression and upregulated the expression of Twist1 protein, which is the key intermediate for EndMT. Based on these results, we hypothesized that FSH may regulates miR-7641/Twist1 pathway to induce EndMT, and finally to increase plaque instability. To verify this, the present project aims to explore the following issues. Firstly, we will explore the relevant sigalings involved in downregulated miR-7641 by FSH. Secondly, that Twist1 is the target of miR-7641 will be confirmed. Thirdly, we will examine the role of miR-7641/Twist1 in FSH-induced EndMT. Finally, we will observe the effect of FSH on EndMT and plaque instability in vivo by using animal model and clinical samples. The present project will provide new insight from EndMT to reveal the effect and molecular mechanism of FSH on plaque instability, which may shed light on novel strategy to prevent the occurence of acute coronary syndrome in postmenopausal women.

女性绝经后动脉粥样硬化(AS)发病率上升。我们新近报道：绝经后高水平FSH促进AS斑块形成。斑块不稳定性是临床急性冠脉事件的病理基础。最新研究表明，内皮-间充质转化(EndMT)可增强斑块不稳定性。预实验显示：FSH可诱导EndMT；可下调内皮miR-7641，上调EndMT关键调控分子Twist1表达。由此提出科学问题：FSH是否通过调控miR-7641/Twist1，进而诱导EndMT发生，增强斑块不稳定性？本项目拟开展：1、研究FSH下调miR-7641的信号机制；2、确认Twist1为miR-7641的调控靶点；3、探讨miR-7641/Twist1在FSH诱导EndMT中的作用；4、在动物模型和临床样本中证实FSH诱导EndMT、增强斑块不稳定性。本项目从FSH诱导EndMT这一新角度出发，揭示FSH促AS斑块不稳定性的分子机制，有望为干预绝经后女性急性冠脉事件发生提供新的策略。

女性绝经后动脉粥样硬化(AS)发病率上升。我们已经报道：绝经后高水平FSH促进AS斑块形成。斑块不稳定性是临床急性冠脉事件的病理基础。最新研究表明，内皮-间充质转化(EndMT)可增强斑块不稳定性,但是FSH与EndMT关系尚不明确。我们的结果表明FSH在体外和体内实验中均可诱导内皮细胞发生EndMT，并进一步观察到FSH可以通过提高ALKBH5 (AlkB同源物5,RNA去甲基化酶)的表达水平来促进EndMT相关转录因子FOXM1蛋白和mRNA的表达，即FSH通过ALKBH5降低FOXM1 m6A水平，导致FOXM1 mRNA稳定性和蛋白质合成水平增加。双荧光素酶报告基因结果表明CREB在FSH介导的ALKBH5表达增加中起关键作用。本研究揭示了FSH对斑块不稳定的影响及其分子机制，为预防绝经后妇女急性冠状动脉综合征的发生提供了新的策略。