基于AMPK/Sirt1-PFKFB3介导的糖酵解途径探讨桃红四物汤在缺血性脑卒中功能性血管新生进程中的作用

如何防止病理血性管新生、促进功能性血管新生是缺血性中风（IS）治疗中亟待解决的科学问题。糖酵解水平是血管新生调节关键因素。AMPK上调PFKFB3磷酸化，适度提升糖酵解水平；Sirt1下调PFKFB3乙酰化，抑制糖酵解异常提升，但AMPK/Sirt1-PFKFB3介导的糖酵解途径在IS血管新生中的作用尚不明确。前期研究证实，中医临床治疗IS常用方桃红四物汤（THSWD）可“祛瘀生新”，促进脑血管新生，抑制血管通透性增高，并上调AMPK、Sirt1表达。据此提出假说：THSWD通过AMPK/Sirt1介导PFKFB3磷酸化和去乙酰化，适度提升糖酵解水平，促进IS功能性血管新生。为验证假说，本项目拟在基因敲除和过表达、慢病毒转染的小鼠与细胞模型上，探索AMPK/Sirt1-PFKFB3干预糖酵解促进IS功能性血管新生的新机制，明确THSWD治疗作用，为IS的中西医临床治疗与药物筛选提供新思路。

Abstract: How to prevent pathological angiogenesis and promote functional angiogenesis is an urgent problem to be solved in treatment of ischemic stroke (IS). The lever of Glycolysis metabolic is a key factor in the regulation of angiogenesis. AMPK can up-regulate PFKFB3 phosphorylation to enhance glycolysis metabolic level moderately. While Sirt1 down-regulates PFKFB3 acetylation to inhibit the abnormal enhancement of glycolysis metabolic level. However, the role of AMPK/Sirt1-PFKFB3-mediated pathway in IS angiogenesis is not clear. Previous studies have confirmed that Tao Hong Si Wu decoction (THSWD), a traditional medicine prescription commonly used in the treatment of IS, has the effect of Stasis-removing and regeneration-promoting. It can also promote angiogenesis, inhibit the increase of vascular permeability, and up-regulate the expression of AMPK and Sirt1. Based on this, it is hypothesized that THSWD can increase the level of glycolysis moderately and promote functional angiogenesis of IS by regulating PFKFB3 phosphorylation and deacetylation through APMK\ Sirt1-mediated pathway. To verify the hypothesis, we try to explore the new mechanism of AMPK/Sirt1-PFKFB3 intervention in glycolysis to promote functional angiogenesis of IS and to clarify the therapeutic effect of THSWD with techniques of gene knockout, overexpression, lentivirus transfection based in mice and cell models, which also provides a new idea for the treatment in Traditional Chinese and Western Medicine and drugs screening of IS.