西洋参茎叶总皂苷调控PKCδ介导的VEGF/PI3K-Akt/eNOS通路改善糖尿病小鼠缺血心肌血管新生的分子机制研究

Diabetes mellitus (DM) could induce ischemic heart disease through impairing the function of vascular endothelial and smooth muscle cells, inhibiting myocardial angiogenesis and reducing blood perfusion. Previous studies have shown that Panax quinquefolius saponin (PQS) ameliorated the cardiac malfunction and abnormal myocardial glucose metabolism caused by chronic myocardial ischemia, increased the arteriole density. The angiogenic role of PQS may be related to the inhibition of PKCδ expression. Therefore, it is of great significance to deepen the mechanism of angiogenic role of PQS for the prevention and treatment of patients with DM complicated with coronary heart disease. In order to solve this problem, the experimental PKCδ homozygous gene knockout mice with both diabetes and acute myocardial infarction will be established to test the beneficial effect of PQS on cardiac function, blood flow perfusion and angiogenesis, and to explore the angiogenic molecular mechanism through VEGF/PI3K-Akt/eNOS, which were well known as the key angiogenic pathway. Therefore, this study will provide experimental basis for the clinical application of traditional Chinese medicine in the prevention and treatment of diabetes mellitus complicated with coronary heart disease.

糖尿病通过影响血管内皮和平滑肌细胞功能，抑制心肌血管新生，减少血流灌注，从而引发缺血性心脏病。课题组前期研究发现，西洋参茎叶总皂苷 (PQS)能够改善小型猪慢性心肌缺血后心功能和心肌代谢，促进缺血心肌血管新生，其机制可能与抑制PKCδ的表达有关。因此，深化研究PQS改善血管新生的分子机理，对预防糖尿病合并冠心病患者心血管事件的发生有重要意义。针对这一问题，本项目通过建立糖尿病合并急性心肌梗死PKCδ-/-小鼠模型，观察PQS对其心功能、血流灌注和缺血心肌血管新生的效应，以VEGF/PI3K-Akt/eNOS信号转导通路为切入点，探讨其促进血管新生的分子机理，可望为中药防治糖尿病合并冠心病的临床应用提供实验依据。

糖尿病患者血管内皮功能受损，血流灌注减少，从而加重心肌缺血。课题组前期研究发现，心悦胶囊的主要有效成分西洋参茎叶总皂苷（PQS）能够促进缺血心肌血管新生，其机制可能与抑制蛋白激酶Cδ（PKCδ）的表达有关。本研究通过建立大鼠2型糖尿病合并急性心肌梗死模型，阐释了PQS对心功能、血流灌注、心肌组织病理学、血管新生及PKCδ介导的VEGF/PI3K-Akt/eNOS通路基因、蛋白的影响，探讨PQS促进缺血心肌血管新生的药理作用及其分子机制。研究结果证实，PQS能够改善2型糖尿病合并急性心肌梗死大鼠的心功能、增加心肌表面血流、减轻心肌组织损伤、增加心肌细胞核密度、减轻心肌组织纤维化，其作用与PQS抑制PKCδ表达，从而促进VEGF、VEGFR2、PI3K、Akt和eNOS的表达相关。本研究明确了PQS促进缺血心肌血管新生的作用并进一步阐明了其分子机制，对促进糖尿病合并冠心病的防治提供了新的实验依据。