黄芪丹参提取物配伍调控PKD1-HDAC5/HDAC7-VEGF轴促血管新生的作用机制研究

Promote angiogenesis has become one of the research focus and important strategy in treating cardiovascular diseases such as myocardial infarction. Recent studies show that protein kinase D1 (PKD1) regulate the proliferation and migration of endothelial cells in the circulatory system by the target protein HDAC5 and HDAC7, involvement of VEGF-induced angiogenesis. Our previous studies also demonstrated that astragalus and salvia extract compatibility improved the cardiac function with the expression regulation of PKD1.Astragalus and salvia are the representative "reinforcing Qi, remove blood stasis" pharmaceutical drugs in treatment of myocardial infarction, yet it is unclear that whether their effect on promoting angiogenesis is through regulation of PKD1 and its target proteins. In the present study, the EPCs cell culture model and myocardial infarction model of rats will be built, the effects on proliferation, migration and angiogenesis ability of EPCs, the myocardial function and pathological changes of post-myocardial infarction rats, and expression of PKD1, HDAC5, HDAC7, VEGF, Flt1 and Flk1 regulated by astragalus and salvia extract compatibility would be observated and analysed, the mechanism of astragalus and salvia extract compatibility promote angiogenesis based on PKD1-HDAC5/HDAC7-VEGF axis might be explained clearly, which probably provides new medical treatment targets for the "Qi-deficiency-blood-stasis" cardiovascular diseases.

促血管新生是治疗心肌梗死等心血管系统疾病的研究热点和重要策略之一。近期研究表明蛋白激酶D1（PKD1）在循环系统中通过靶标蛋白HDAC5和HDAC7调节内皮细胞的增殖和迁移，参与VEGF诱导的血管生成过程。我们发现黄芪丹参提取物配伍有通过调控PKD1的表达而改善梗死后心肌组织的功能。黄芪丹参作为气血并治治疗心肌梗死的代表性药物，是否通过调控PKD1及其效应蛋白而促进血管生成还不清楚。本研究拟通过离体大鼠EPCs模型和在体大鼠心肌梗死模型，观察黄芪丹参提取物配伍对EPCs增殖、迁移和血管形成能力的影响，大鼠梗死后心肌功能和病理组织的改变以及PKD1、HDAC5、HDAC7、VEGF、Flt1、Flk1等效应蛋白的表达变化，初步阐明黄芪丹参提取物配伍调控PKD1-HDAC5/HDAC7-VEGF轴促心肌梗死后血管新生的作用机制，为"益气化瘀"类药物治疗"气虚血瘀"型心血管疾病提供新的作用靶点。

心肌梗死的修复和预后与心肌组织血管的功能状态关系密切，迅速而有效地建立侧支循环对改善梗死区的血液供应及梗死区心肌的存活均有极其重要的意义。黄芪丹参是气血并治治疗心肌梗死的代表性药物之一。之前的文献报道和课题组研究证实，蛋白激酶D1（PKD1）在循环系统中通过靶标蛋白HDAC5和HDAC7调节内皮细胞的增殖和迁移，参与VEGF诱导的血管生成过程，而黄芪丹参提取物配伍有通过调控PKD1的表达而改善梗死后心肌组织的功能。.本研究通过离体培养骨髓源性EPCs，从体外细胞培养实验角度，分别观察了黄芪丹参提取物配伍对骨髓源性EPCs粘附、增殖、迁移和血管形成能力和对PKD1、HDAC5、HDAC7、MEF2、VEGF、Flt1和Flk1表达的影响。并通过在体建立大鼠心肌梗死模型，观察黄芪丹参提取物配伍对心梗大鼠心肌组织形态学的影响以及通过对PKD1及其靶标蛋白表达的调控促大鼠心肌梗死后血管新生的影响，阐释益气化瘀通络中药促血管新生的作用机制，即通过调控PKD1-HDAC5/HDAC7-VEGF轴主要效应蛋白PKD1、HDAC5、HDAC7、MEF2等的表达、上调VEGF及其受体Flt1和Flk1的表达，促血管新生，从而改善梗死区的血供，改善心脏功能。为中药治疗心肌梗死等缺血性心脏病提供了一种新的思维和途径，为“益气化瘀”类药物治疗“气虚血瘀”型心血管疾病提供了新的作用靶点。