PIN1调控糖代谢重编程在动脉粥样硬化斑块稳定性中的作用及机制研究

Macrophage polarization-mediated inflammatory response contributes to atherosclerotic plaque vulnerability. Energy metabolism is the material basis of macrophage M1/M2 polarization. PKM2-mediated glucose metabolism reprogramming can promote macrophage M1 polarization and inhibit M2 polarization. PIN1 is an important protein that affects the nuclear translocation of PKM2 and plays an important role in glucose metabolism reprogramming. PIN1 promotes inflammatory response and myocardial remodeling, but its role in plaque stability has not been reported. We have found that PIN1 was highly expressed in plaque tissues and LPS-stimulated macrophages. Moreover, PIN1 inhibition reduced PKM2 nuclear translocation in macrophages and decreased secretion of inflammatory cytokines. Thus, we hypothesized that PIN1 might play an important role in plaque instability by regulating PKM2-mediated glucose metabolism reprogramming as well as macrophage polarization. The present study is designed to explore the role of PIN1 in plaque stability. Our results may provide potential molecule targets as well as novel ideas for the treatment of vulnerable plaques.

巨噬细胞M1/M2极化介导的炎症反应是动脉粥样硬化斑块易损的关键。能量代谢是巨噬细胞M1/M2极化的物质基础，糖代谢关键酶PKM2介导的糖代谢重编程能够促进巨噬细胞M1极化、抑制M2极化。PIN1是影响PKM2核转位发挥糖代谢重编程效应的重要蛋白，能够促进炎性反应及心肌重构，但在斑块稳定性中的作用尚无报道。申请者前期发现PIN1在斑块组织及LPS刺激的巨噬细胞中均显著高表达，并且抑制PIN1能减少巨噬细胞中PKM2的核转位，降低炎性因子的分泌。据此提出如下假说“PIN1通过调控PKM2的核转位发挥糖代谢重编程效应，介导巨噬细胞M1/M2极化，导致斑块不稳定”。本课题拟运用多种实验方法，体内外研究相结合，研究PIN1在斑块稳定性中的作用及分子机制。本研究将从糖代谢重编程角度为干预易损斑块提供新思路、新靶点。

巨噬细胞M1/M2极化介导的炎症反应是动脉粥样硬化斑块易损的关键。能量代谢是巨噬细胞M1/M2极化的物质基础，糖代谢关键酶PKM2介导的糖代谢重编程能够促进巨噬细胞M1极化、抑制M2极化。PIN1是影响PKM2核转位发挥糖代谢重编程效应的重要蛋白，能够促进炎性反应及心肌重构，但在斑块稳定性中的作用尚无报道。项目组主要研究了PIN1通过促进PKM2核转位继而调控发挥糖代谢重编程效应，促进巨噬细胞M1极化、抑制M2极化，加剧动脉粥样硬化斑块不稳定。项目组发现1）PIN1高表达于ApoE-/-小鼠颈动脉斑块组织中；2）糖代谢关键蛋白PKM2大量表达于斑块组织中的巨噬细胞；3）抑制PKM2核转位能够减少巨噬细胞向M1极化、提高斑块稳定性；4）在巨噬细胞中抑制PIN1能够降低PKM2核转位、减少炎性因子TNF-α、IL-1β的分泌；5）巨噬细胞特异性敲除PIN1能够减少巨噬细胞向M1极化、提高斑块稳定性。我们的研究表明PIN1/PKM2轴驱动的糖代谢重编程是巨噬细胞极化的重要因素，为易损斑块提供了新的治疗靶点。