我们前期研究发现AngII刺激血管内皮细胞由自噬向衰老转化，提示AngII可能通过影响内皮细胞自噬途径，进而引发各种衰老相关的心血管疾病。研究表明Class III PI3K是细胞自噬诱导阶段最关键的调节分子。我们推测Class III PI3K经AngII刺激活化，通过启动细胞自噬途径，负反馈调节AngII诱导的细胞衰老。因此本项目拟研究AngII活化Class III PI3K介导细胞自噬的分子机制；探讨Class III PI3K催化亚单位Vps15是否是AngII诱导的AT1受体内化、运输及降解，调节细胞自噬和衰老的关键因子；动物体内研究Vps15对AngII诱导高血压以及其他因素导致高血压是否通过影响内皮细胞自噬活性发挥调节作用。本课题将阐明Class III PI3K负反馈调节AngII诱导血管内皮细胞衰老的分子机制，为阻断AngII对内皮细胞的促衰老作用提供实验依据。

Our previous results showed the process from autophagy to senescence in vascular endothelial cells induced by AngII, which indicated that AngII probably elicits aging-associated cardiovascular diseases by affecting the autophagic pathway of endothelial cells. It is reported that Class III PI3K is the most critical regulatory molecular in the induction of cell autophagy. We propose that Class III PI3K is activated by AngII to start autophagy signalings and participates in the negative feedback regulation on cell senescence induced by AngII. In this project, the molecular mechanism of cell autophagy mediated by Class III PI3K will be explored in AngII stimulated endothelial cells. Whether Vps15, the catalytic subunit of Class III PI3K, is the crucial regulator of AT1 receptor internalization, transportation and degradation in the process of cell autophagy and senescence will be studied in AngII stimulated endothelial cells. In vivo animal models of AngII stimulated hypertension or hypertension induced by other factors will be estabished to investigate the roles of Vps15 in the autophagic activity of endothelial cells. In summary, the molecular mechanism of the negative feedback regulation on senescence by Class III PI3K in AngII stimulated vascular endothelial cells will be elucidated in this project, which is a necessary premise to the prevention of AngII in the vascular endothelial senescence.