基于血管生成探索补阳还五汤异病同治的生物学基础

The project is grounded on traditional Chinese medicine theory, and puts forward that treating different diseases with same method is based on diseases of some specific classes or systems. A classical prescription Buyang Huanwu Decoction (BHD) is chosen as the target prescription, and vascular disease as the entry point. The project is aimed to study the angiogenic role of BHD on mouse models of myocardial infarction, focal cerebral ischemia / reperfusion injury, diabetic hind limb ischemia, and on Qi deficiency and blood stasis model of these three diseases seperately. The project will preliminarily clarify that the modern biological basis of treating different diseases with same method using BHD is mainly related to its angiogenic effect, and to provide new approaches for the prevention and treatment of ischemic diseases with traditional Chinese medicine and for the study of the correspondence between syndromes and prescriptions. Meanwhile, Caveolin-1 gene knockout mice will be used in the study to elucidate that the possible mechanism of the angiogenic effect of BHD may be that caveolin -1 could modulate vascular endothelial growth factor (VEGF ) signaling pathway through regulate VEGF receptor-2, and thus provide new ideas for the clinical and basic research of integrated traditional Chinese and Western medicine. Finally, to verify the hypothesis of this project: treating different diseases with same method using BHD is mainly through a common pathological pathway of vascular diseases, and the modern biological foundation is mainly related to its angiogenic effect. The function mechanism is achieved mainly through the regulation of VEGF signaling pathways by caveolin -1, and thus provides experimental evidence for the biological basis of treating different diseases with same method of BHD.

该项目立足中医传统理论，提出异病同治是基于特定的某类或某系统疾病，以经典名方补阳还五汤（BHD）作为目标方剂，选择血管性疾病作为切入点，阐明BHD对心肌梗死、局灶性脑缺血/再灌注损伤和糖尿病下肢缺血小鼠模型及这3种不同疾病气虚血瘀病证结合模型的促血管生成作用，揭示BHD异病同治的现代生物学基础主要与促进血管生成有关，为中医药防治缺血性疾病及方证相应研究提供新的途径。同时，采用小凹蛋白-1基因敲除小鼠，阐明BHD异病同治促血管生成的机制主要是小凹蛋白-1通过调控血管内皮细胞生长因子（VEGF）受体-2而调节VEGF的信号通路，为异病同治中西医结合临床基础研究提供新的思路。最终验证课题假说：BHD异病同治主要是针对血管性疾病的共同病理环节，其现代生物学基础可能与促进血管生成有关，作用机制主要是通过小凹蛋白-1调节VEGF信号通路来实现的，为BHD异病同治的生物学基础提供实验依据。

项目的背景：该项目立足中医传统理论，提出异病同治是基于特定的某类或某系统疾病，以经典名方补阳还五汤（BHD）作为目标方剂，选择血管性疾病作为切入点，阐明BHD对心肌梗死、局灶性脑缺血/再灌注损伤和糖尿病下肢缺血小鼠模型的促血管生成作用，揭示BHD异病同治的现代生物学基础主要与促进血管生成有关，为中医药防治缺血性疾病及方证相应研究提供新的途径，为BHD异病同治的生物学基础提供实验依据。.主要研究内容： (1)补阳还五汤对心肌梗死小鼠模型的心脏保护作用及其机制；（2）补阳还五汤对心肌梗死小鼠的促血管生成作用是否与小凹蛋白（cav-1）/血管内皮生长因子（VEGF）通路想关。(3)补阳还五汤对脑缺血/再灌注损伤大鼠模型的神经保护作用；（4）探讨补阳还五汤对脑缺血/再灌注大鼠的促血管生成作用是否与组织沉默信息调节因子1（SIRT1）/VEGF通路相关。(5)补阳还五汤对糖尿病下肢缺血小鼠血运重建的影响及其相关机制。.重要结果：(1)补阳还五汤可改善心肌梗死小鼠的心功能及梗死面积；(2)补阳还五汤能通过CAV-1/VEGF通路促进心肌梗死小鼠的血管新生；(3)补阳还五汤可改善缺血/再灌注后大鼠模型神经功能缺损症状，上调SIRT1以及VEGF的表达，从而促进血管生成；（4）侧脑室注射EX527后，补阳还五汤的促血管生成作用显著降低，进一步明确了其神经保护机制的靶点是通过上调SIRT1表达实现的；(5)补阳还五汤能通过活化NRF2促进糖尿病下肢缺血小鼠的血运重建。.关键数据及其科学意义：项目阐明了补阳还五汤在局灶性脑缺血/再灌注损伤、心肌梗死、和糖尿病下肢缺血小鼠模型中的促血管生成作用，为中医药治疗缺血性疾病提供潜在的治疗靶点和开辟新的研究思路；阐明了补阳还五汤对缺血性疾病的保护作用及促进缺血区域血管生成的治疗学机制可能与调节SIRT1/VEGF、CAV-1/VEGF、AKT/GSK3β/NRF2通路有关，为BHD异病同治的生物学基础提供实验依据。