衰老诱发动脉粥样硬化新视角：SIRT6调控血管内皮细胞EndMT

Aging is becoming a key social problem in China. Cardiovascular diseases are the leading cause of death in the elderly. Studies have shown that the incidence of atherosclerosis increases with age. However, the mechanism of age-related atherosclerosis is still unclear. Endothelial to mesenchymal transition (EndMT) is a crucial process for the development and progress of atherosclerosis. Our preliminary data showed that EndMT occured in aged endothelial cells. Meanwhile, EndMT was associated with downregulation of SIRT6 and depletion of SIRT6 induced EndMT. To our knowledge, the machanism of age-related EndMT has not been previously described and the effect of age-related EndMT on endothelial cells is unclear. Based on our preliminary findings, we will further investigate the occurrence of EndMT in aged endothelial cells, the regulatory mechanism of SIRT6 in EndMT process, and the effect of EndMT reversal on the improvement of endothelial function and repression of age-related atherosclerosis. Our project puts forward the idea that regulating EndMT through SIRT6 is expected to be an effective treatment for age-related atherosclerosis. Our program will provide important clues for the prevention and treatment of age-related cardiovascular diseases.

老龄化是我国的重要社会问题，心血管疾病是威胁老年人生命健康的“头号杀手”。研究表明动脉粥样硬化的发病率随着年龄增长而逐渐增加，但相关机制还不清楚。血管内皮-间质转化（EndMT）在动脉粥样硬化发生发展中有关键作用，申请人近期研究发现内皮细胞在衰老过程中发生了EndMT，同时SIRT6在EndMT发生过程中明显下调并且抑制SIRT6可促进EndMT的发生。然而，衰老诱发EndMT的调控机制及其对血管内皮结构和功能的影响还未有报道。本课题将在申请人前期工作的基础上深入研究衰老诱发EndMT的发生过程，SIRT6对EndMT的调控作用及机制，并进一步探讨逆转EndMT能否改善内皮功能进而治疗衰老动脉粥样硬化。本课题创新性提出以SIRT6调控血管内皮细胞EndMT为关键点的衰老动脉粥样硬化防治新理念，为老年心血管疾病提供新的治疗靶点和思路，具有重要的理论意义和应用价值。

本项目按计划任务书顺利完成，老龄化是我国的重要社会问题，心血管疾病是威胁老年人生命健康的“头号杀手”。研究表明动脉粥样硬化的发病率随着年龄增长而逐渐增加，但相关机制还不清楚。血管内皮间质转化（endothelial to mesenchymal transition，EndMT）在动脉粥样硬化发生发展中有关键作用，SIRT6是衰老相关基因。本研究目的在于探究SIRT6调控血管内皮细胞EndMT及其参与衰老相关动脉粥样硬化的作用。实验发现衰老的血管内皮细胞发生EndMT，SIRT6在衰老的血管内皮细胞中表达下调，在内皮细胞中用siRNA敲减SIRT6能诱发EndMT，表现为低表达SIRT6的内皮细胞形态由卵圆形变成了长梭形，且内皮细胞特异分子VE-cadherin和CD31表达降低，而间质细胞特异分子α-SMA和FSP1表达升高，内皮细胞通透性实验表明低表达SIRT6的细胞通透性明显增强，这些结果表明SIRT6介导了衰老诱发的EndMT。进一步研究发现，SIRT6可以结合到长链非编码RNA-MALAT1的启动子上并对其表达产生负调控作用。因此我们得到结论，在内皮衰老过程中，SIRT6表达降低导致EndMT和动脉粥样硬化，这一发现为衰老动脉粥样硬化防治提供了新靶点。除此以外，我们还发现EndMT参与介导了尼古丁诱导的动脉粥样硬化，尼古丁通过α7nAChR-Snail信号通路调控EndMT，阻断α7nAChR-Snail信号通路能改善尼古丁诱导的动脉粥样硬化。免疫功能障碍和氧化应激是动脉粥样硬化的发病机制之一，金叶女贞是一种观赏灌木，但其药用价值却未被开发，我们提取分离了金叶女贞果实多糖（Ligustrum vicaryi L. fruit polysaccharides，LVFP）并发现其具有免疫调节和抗氧化活性，这一发现为动脉粥样硬化临床治疗提供了新的药物。