ANXA2介导的整合素α5转位入脂筏激活在早期动脉粥样硬化中的作用及机制研究

Atherosclerosis is a focal disease with the deposition of lesion plaque under the middle and large arteries, which often happen in bifurcations and curved regions of artery vessel characterized by atherogenesis flow. Endothelial cell inflammatory response to shear stress is considered to be one of the early reasons for its occurrence. Our previous studies demonstrated that disturbed flow induced translocation of integrin α5 (α5) to the cell membrane lipid rafts and activated, and promoted endothelial cell dysfunction through c-Abl/YAPY357 signaling and inflammasome activation. However, the molecular mechanism of α5 translocated into lipid rafts is still unclear. In the preliminary study, proteomics analysis from lipid rafts and whole cell lysis showed that annexin A2(ANXA2) get the highest score. Based on those data, the hypothesis of the current project is that disturbed flow induced translocation of α5 to the lipid rafts via ANXA2. To achieve this goal, we will investigate the relationship between ANXA2 and α5, the role of endothelial cells activation under shear stress and inflammation response at cellular level and the underlying mechanism; In addition, we will establish the endothelial cell-specific ANXA2 deficient atherosclerosis mice models, and observe the lesion area and plaque inflammation reaction in those area. This study may extend our knowledge of the mechanisms of Atherosclerosis and potentially contribute to the development of novel therapeutic approaches to it.

动脉粥样硬化（As）是一种局灶性大中动脉内膜下斑块沉积的病变，常见于发生湍流的动脉血管分叉或弯曲处。内皮细胞炎症反应被认为是其病变早期原因之一。前期研究表明在血管内皮细胞湍流促使整合素α5（α5）向细胞膜脂筏转位并激活，通过c-Abl/YAPY357信号通路和激活炎性小体促进内皮细胞激活。然而湍流调控α5转位入脂筏的具体机制尚不清楚。预实验结果发现，湍流处理下转位入脂筏的蛋白及α5结合蛋白的蛋白组学综合分析提示膜联蛋白ANXA2关系最为密切。因此，本项目的科学假说为：ANXA2介导了湍流引起的α5转位入脂筏并激活。我们将在细胞水平研究湍流促进ANXA2与α5结合，以及ANXA2对内皮细胞激活与炎症反应的影响和机制；此外我们将建立内皮细胞特异性敲除ANXA2的As模型鼠，观察斑块区域炎症反应情况。以期完善湍流促进As的分子机制并为其治疗提供新的潜在性靶点。

动脉粥样硬化是一类慢性进行性炎症性疾病，其好发于血管的分叉处及弯曲处，这些部位的血流形式主要是不稳定的湍流。内皮细胞炎症反应被认为是其病变早期原因之一。前期研究表明在血管内皮细胞湍流促使整合素α5（α5）向细胞膜脂筏转位并激活，通过c-Abl/YAPY357信号通路和激活炎性小体促进内皮细胞激活。然而湍流调控α5转位入脂筏的具体机制尚不清楚。预实验结果发现，湍流处理下转位入脂筏的蛋白及α5结合蛋白的蛋白组学综合分析提示膜联蛋白ANXA2关系最为密切。机制研究表明湍流抑制Annexin A2的Tyr24磷酸化，使Annexin A2构象改变，促进了 Annexin A2与integrin α5的结合及转位，通过Piezo1-Ca2+-PTP1B通路介导integrin α5的激活。进一步揭示了一种新的内皮细胞机械转导分子机制，从而为动脉粥样硬化的治疗提供靶点。我们的研究论文发表在Circ Res上。整体上，发表基金标注论文3篇，其中两篇为第一作者。