组蛋白去乙酰化酶HDAC3去巴豆酰化修饰对动脉粥样硬化中EndMT的调控及机制研究

Recent studies showed that endothelial-to-mesenchymal transition (EndMT) contributes to the initiation and progression of atherosclerosis (AS) and plaque stabilization. The histone deacetylase HDAC3-mediated post-translational modification is a new way of regulating EndMT. We found that HDAC3 promoted EndMT in vascular endothelial cells, and the levels of crotonylation and acetylation of cells were increased during EndMT. However, whether EndMT is regulated by HDAC3-mediated decrotonylation or deacetylation in atherosclerotic plaques remains elusive. Therefore, we hypothesize that HDAC3 regulates EndMT in atherosclerotic plaques through the decrotonylation or deacetylation activity. In the present study, we first investigate the effect of HDAC3 on EndMT during atherogenesis in mice and vascular endothelial cells. Then, we screen and determine the differential proteins of crotonylation and acetylation, and related modification sites regulated by HDAC3 through modification proteomics. Further study will be performed to determine the modification relationships of HDAC3 between decrotonylation and deacetylation in AS. The study focuses on the effect of post-translational modification on EndMT and provides the experimental and theoretical foundation for pathogenesis and prevention and treatment of AS.

最新报道：内皮间质转分化（EndMT）与动脉粥样硬化（AS）发生发展和斑块稳定性密切相关，而组蛋白去乙酰化酶HDAC3介导的翻译后修饰是调控EndMT新机制。课题组发现：HDAC3促进血管内皮细胞EndMT，且EndMT过程中细胞蛋白巴豆酰化和乙酰化水平发生变化，但HDAC3是否通过去巴豆酰化或去乙酰化调控AS斑块中EndMT仍不清楚。因此假设：HDAC3调控AS斑块中的EndMT，机制与其去巴豆酰化或去乙酰化有关。本项目首先在动物和细胞水平，研究HDAC3通过调控EndMT参与AS的发生发展和斑块稳定性。然后应用蛋白质修饰组学，筛选HDAC3调控的差异巴豆酰化和乙酰化修饰蛋白及位点，进而明确HDAC3通过巴豆酰化或乙酰化修饰调控AS斑块中EndMT。进一步研究HDAC3去巴豆酰化和去乙酰化修饰之间关系。本研究以调控EndMT关键蛋白的翻译后修饰为切入点，为阐明AS发病机制及防治提供依据。

最新报道：内皮间质转分化（EndMT）与动脉粥样硬化（AS）发生发展和斑块稳定性密切相关，而组蛋白去乙酰化酶HDAC3介导的翻译后修饰是调控EndMT新机制。课题组前期发现：HDAC3促进血管内皮细胞EndMT，且EndMT过程中细胞蛋白巴豆酰化和乙酰化水平发生变化，但HDAC3是否通过去巴豆酰化或去乙酰化调控AS斑块中EndMT仍不清楚。因此，本项目以HDAC3内皮特异性敲除和ApoE敲除的小鼠和血管内皮细胞为研究对象，研究了HDAC3通过翻译后修饰对AS中EndMT和血管炎症的调节及相关机制。研究发现，HDAC3特异性抑制剂和HDAC3内皮特异性敲除均能减轻ApoE敲除小鼠AS发生发展和斑块EndMT发生，并且HDAC3通过去巴豆酰化和去乙酰化修饰靶蛋白调控AS和血管内膜增生中EndMT。此外，在研究过程中还发现HDAC3与Ⅲ类组蛋白去乙酰化酶成员SIRT6存在相互作用，因此进一步研究了SIRT6通过EndMT对血管内膜炎症的调控作用，并发现一些中药单体以HDAC3和SIRT6为靶点，发挥对AS的保护作用。. 以上研究结果共发表12篇SCI论文和1篇中文核心期刊。此外，参加4次国内学术会议，发表4篇会议摘要；培养研究生5名，研究成果获得4项奖项和1项授权专利。该研究不仅为HDAC3对AS中EndMT调节提供依据，阐明HDAC3通过翻译后修饰调控EndMT的相关机制，而且为临床AS的治疗和抗AS新药开发提供实验依据和新的思路。