基于Warburg效应调控巨噬细胞NLRP3炎症小体活化探讨补阳还五汤抗动脉粥样硬化的作用机制

巨噬细胞的胞质内感受器“NLRP3炎症小体”活化，介导并放大动脉粥样硬化（AS）炎症反应，加速AS进程。鉴于糖代谢重编程引起的“Warburg效应”促进NLRP3炎症小体活化，调控糖代谢成为抑制炎症以延缓AS的新思路。中医学认为气虚血瘀是AS主要病机，前期研究证实益气活血方药“补阳还五汤”可抑制NLRP3炎症小体活化、调控糖代谢，但其调控糖代谢与抑制炎症反应之间是否存在关联尚待进一步阐释。故提出假说：基于调控糖代谢Warburg效应抑制巨噬细胞NLRP3炎症小体活化，是补阳还五汤抗AS的潜在机制。以ApoE-/-小鼠AS模型、ox-LDL激活的巨噬细胞为研究对象，通过代谢组学、液相芯片、基因沉默/过表达等技术，在体明确该方抑制NLRP3炎性小体活化与调控Warburg效应之间的相关性，离体阐释其具体作用靶点。本研究结果可进一步丰富益气活血的理论内涵，所涉及信号蛋白有望成为抗AS的重要靶点。

Atherosclerosis (AS) is an inflammatory pathological process that closely associates with NLRP3 inflammasome activation in macrophages. It was shown that the “Warburg effect”, which is used by some cancer cells to reprogram glucose metabolism under aerobic conditions to apply glycolysis rather than oxidative phosphorylation, is involved in multiple steps of NLRP3 inflammasome activation. This indicates that regulating glucose metabolism could potentially block the inflammatory process in AS. Traditional Chinese Medicine (TCM) attributes AS to “Qi deficiency and blood stasis”. Therefore,“Bu Yang Huan Wu decoction”, which is a classical representative formulary of “Enriching qi and activating blood”, is demonstrated to be able to inhibit NLRP3 inflammasome activation and to alleviate lactic acidosis in our preliminary study. However, whether its effects on NLRP3 inflammasome are due to its role in glucose metabolism is still to be elucidated. So, we propose that the beneficial effect of Bu Yang Huan Wu decoction in treating AS might be through regulating the Warburg effect to inhibit NLRP3 activation in Macrophages. To explore the mechanism of Bu Yang Huan Wu decoction in treating AS and its target in regulating Warburg effect and inhibit NLRP3 inflmmasome, analytical tools include metabonomics, suspension array, gene knock out and over expressions will be applied using apoE-/- mice and ox-LDL activated macrophages as in vivo and in vitro models respectively. This project is to provide scientific evidence to the concept of “Enriching qi and activating blood” and the proteins being identified in the signal pathway of this study could be used as targets to treat AS in the future.