STAT3/MAVS/NLRP3炎症小体信号通路在动脉粥样硬化中的作用

动脉粥样硬化是一种慢性炎症疾病。近期研究显示固有免疫信号通路异常参与了动脉粥样硬化的发生与发展。MAVS是固有免疫信号通路中的关键蛋白，可以介导炎症的发生。我们的预实验结果显示：MAVS促进了血管内皮细胞及巨噬细胞的炎症反应；血管内皮细胞高表达MAVS可以显著上调NLRP3的表达，提示MAVS可能通过激活NLRP3炎症小体介导血管的炎症反应。进一步的信息学分析发现，在MAVS启动子区有三个转录因子STAT3的结合位点，在血管内皮细胞抑制STAT3活性，可以显著降低MAVS的表达，提示STAT3可能是MAVS上游的调控分子。因此我们推测：MAVS在STAT3的调控下，通过激活NLRP3炎症小体参与了动脉粥样硬化的发生和发展。本课题拟在动物、细胞和分子水平，通过基因敲除技术和特异性抑制剂，深入研究MAVS在动脉粥样硬化中的作用及机制，为临床干预动脉粥样硬化及其相关疾病提供新的可能靶点。

Atherosclerosis is a chronic inflammatory disease. Atherosclerotic lesion progression relied on persistent chronic inflammation in the artery wall. Abnormal innate immunity has been thought to contribute to the initiation and progression of atherosclerosis. As the key protein in the innate immunity signaling, MAVS showed pro-inflammatory actions in many noninfectious diseases. However its role in atherosclerosis has not been well studied. Here our preliminary data indicated that MAVS contributed to the inflammation in both vascular endothelial cell and macrophage. More importantly, we found overexpression of MAVS in endothelial cells increased the protein expression of NLRP3, suggesting that MAVS may mediate vascular inflammation by activating NLRP3 inflammasome. Next, through bioinformatics analysis, we found three STAT3 binding sites in the promoter region of MAVS. Meantime, in vascular endothelial cells, STAT3 inhibitor could decrease the expression of MAVS. These data indicated that transcription factor STAT3 may serve as an upstream regulatory molecule of MAVS. Thus we proposed the research hypothesis: STAT3-drived MAVS could be of importance in the initiation and progression of atherosclerosis through activating NLRP3 inflammasome. In the present proposal, employing the atherosclerotic animal models in vivo and cell models in vitro, we will fully investigate the role of MAVS in the pathogenesis of atherosclerosis using the genetic and pharmacological strategies. This research work will provide the new insights and potential targets for clinical intervention of atherosclerosis and atherosclerosis-related diseases.