糖尿病缺血/再灌注后血糖波动对心肌微血管p38MAPK通路的影响及益气养阴活血配伍干预机制研究

Abnormal myocardial microvessel angiogenesis and myocardial microvascular endothelial dysfunction are the important pathological mechanisms of long-term poor prognosis in diabetes mellitus patients after ischemia/reperfusion (I/R). Recently, the increased amplitude of blood glucose fluctuation after ischemia/reperfusion (I/R) has been linked to increased death and poor prognosis, however, the mechanism is still unknown, meanwhile there is currently lack of effective medicine. Our previous study shows that Yiqi Yangyin Huoxue Chinese Herb has significant protective effects on coronary vascular lesions and endothelial function injury induced by blood glucose fluctuations, but its impacts on microvascular angiogenesis and endothelial function are still unknown. The activation of p38MAPK signal transduction has close relationship with endothelial injury and angiogenesis by inducing cell migration, enhancing inflammation and oxidative stress. This study chooses blood glucose fluctuation after I/R as the entry point, builds hypoxia/reoxygenation human cardiac microvascular endothelial cells model with blood glucose fluctuation in vitro and type 2 diabetes rat mode with blood glucose fluctuation after I/R in vivo, while taking the Yiqi Yangyin Huoxue Chinese Herb as the intervention drug, focusing on the p38MAPK signal transduction, we aim to investigate the effects of blood glucose fluctuation after I/R on myocardial microvessel angiogenesis and endothelial function and the intervention of Yiqi Yangyin Huoxue Chinese herbs in diabetes with acute myocardial infarction, which may offer experimental evidence for the clinical application of Yiqi Yangyin Huoxue Chinese herbs in the future.

心肌微血管新生和内皮细胞功能损伤是糖尿病患者缺血/再灌注（I/R）后预后不良的重要病理环节，I/R后血糖波动者预后更差，但其机制尚不明确，临床亦缺乏有效的干预药物。前期研究发现益气养阴活血中药配伍对血糖波动诱导的冠脉大血管病变和内皮功能损伤具有显著疗效，但其对心肌微血管损伤的影响及机制研究仍欠缺。p38MAPK信号通路的激活可诱导细胞迁移、放大炎症反应及氧化应激水平，与血管新生和内皮损伤关系密切。基于此，本研究拟以I/R后血糖波动为切入点，通过血糖波动诱导I/R后大鼠和缺氧/复氧后人心脏微血管内皮细胞构建体内外模型，以益气养阴活血中药配伍为干预药物，聚焦于p38MAPK信号通路，分别从动物和细胞层次研究I/R后血糖波动对心肌微血管新生和内皮细胞功能的影响及益气养阴活血配伍的干预效应机制。本项目将为今后合理应用益气养阴活血中药防治糖尿病急性冠脉病变提供科学依据。

心肌微血管新生和内皮功能损伤是糖尿病患者缺血/再灌注（I/R）后预后不良的重要病理环节，I/R后血糖波动者预后更差，但其机制尚不明确，临床亦缺乏有效的干预药物。前期研究发现益气养阴活血中药配伍对血糖波动诱导的冠脉大血管病变和内皮功能损伤具有显著疗效，但其对心肌微血管的影响及机制研究仍欠缺。p38MAPK信号通路的激活可诱导细胞迁移、放大炎症及氧化应激反应，与血管新生和内皮损伤关系密切。本研究以I/R后血糖波动为切入点，通过构建血糖波动诱导I/R后大鼠和缺氧/复氧后人心脏微血管内皮细模型，并以益气养阴活血中药配伍进行干预，研究发现：① I/R后血糖波动能够加剧心肌微血管新生异常及内皮细胞功能损伤；②I/R后血糖波动能进一步加重心脏微血管内皮细胞及心肌组织氧化应激反应、促进炎症因子释放；③p38MAPK通路参与了血糖波动介导的I/R后心肌微血管新生及内皮细胞功能损伤过程；④益气养阴活血中药配伍（PQS+TMP）均能不同程度改善血糖波动介导的I/R后心肌微血管新生和内皮细胞损伤，其机制与调控p38MAPK通路相关。本研究的开展为明确I/R后血糖波动造成AMI患者远期预后不良的机制，加强I/R后血糖稳态调控，促进益气养阴活血中药的临床应用提供了实验依据。