血糖波动对2型糖尿病大鼠急性心肌梗死后心肌重塑和血栓形成的影响及益气养阴活血配伍的干预效应研究

The prognosis of cardiovascular events in type 2 diabetes mellitus (T2DM) is equal to that found in patients with coronary heart diseases (CHD) not associated with T2DM. Acute myocardial infarction (AMI) is the highest mortality of cardiovascular diseases. Recently, the increased amplitude of blood glucose fluctuation in diabetes mellitus patients complicated with acute myocardial infarction could significantly affect heart function and prognosis of myocardial infarction patients. However, the mechanism is still unknown. Myocardial remodeling is the important pathological mechanism of heart failure and heart rupture after AMI, while thrombosis is the vital cause of cardiovascular events recurrence. Then, whether blood glucose fluctuation have influence on myocardial remodeling and thrombosis formation? Yiqi Yangyin Huoxue is the basic principle of treatment for diabetic angiopathies. And, does it have effect on myocardial remodeling and thrombosis formation after AMI? In this study, we build ischemia hypoxia myocardial cells with blood glucose fluctuation model in vitro and type 2 diabetes rats with acute myocardial infarction and coronary microthrombosis with blood glucose fluctuation rats model. To observe the myocardial cell activity, apoptosis, heart function, myocardial remodeling and thrombosis formation, and the protein expressions of Jak/Stat pathway were investigated after intervention with Yiqi Yangyin Huoxue Chinese herbs in order to investigate the effects of blood glucose fluctuation on myocardial remodeling and thrombus formation and the intervention of Yiqi Yangyin Huoxue Chinese herbs in type 2 diabetic rats with acute myocardial infarction. Our study could provide the experimental basis of clinical blood glucose fluctuation control, and promote the application of Yiqi Yangyin Huoxue Chinese herbs in prevention and treatment of acute coronary artery lesions.

2型糖尿病是冠心病的等危症，急性心肌梗死（AMI）是死亡率极高的心血管疾病。近来发现，糖尿病并发AMI患者血糖波动程度增加可显著影响其心脏功能及预后，但机制未明。心肌重塑是AMI后心脏破裂、心力衰竭的重要病理机制；血栓形成是再次发生心血管事件的重要环节。那么，血糖波动对AMI后心肌重塑及血栓形成是否具有影响？益气养阴活血法是治疗糖尿病血管病变的基本治则，其对AMI后心肌重塑及血栓形成具有怎样的作用？本研究拟通过体外构建缺血缺氧心肌细胞血糖波动模型，体内构建2型糖尿病AMI及冠脉微血栓大鼠血糖波动复合模型，用益气养阴活血配伍进行干预，观察心肌损伤凋亡、心功能、心肌重塑及血栓形成情况、Jak/Stat通路表达情况，探讨血糖波动对2型糖尿病大鼠AMI后心肌重塑和血栓形成的影响及益气养阴活血配伍的干预效应，为临床进行AMI后血糖稳态控制提供实验依据，促进益气养阴活血中药在急性冠脉病变防治中的应用。

2型糖尿病是冠心病的等危症，急性心肌梗死（AMI）严重威胁人类健康，是心血管系统中死亡率最高的疾病之一。临床研究表明，糖尿病合并AMI患者血糖波动幅度增加可严重影响患者心功能及预后，但其具体机制尚不明确。心室重构是导致AMI后心脏破裂、心力衰竭的重要病理机制，而血栓形成是再次发生心血管事件的重要环节。此外，前期研究结果显示血糖波动具有显著诱导2型糖尿病大鼠血管内皮损伤及血小板活化的效应，益气养阴活血中药能拮抗该作用。基于此，本项目提出血糖波动可能通过影响AMI后心肌重塑及血栓形成，益气养阴活血中药对血糖波动诱导AMI后心肌重塑和血栓形成具有显著抑制效应的假说。本研究借助体外缺血缺氧心肌细胞血糖波动复合模型，给予益气养阴中药组分：西洋参茎叶总皂苷（PQS）、活血化瘀中药组分：川芎嗪（TMP）和芍药苷（PF）以及JAK2/STAT3信号通路抑制剂AG490干预发现：① 缺血缺氧可造成心肌细胞活力下降、细胞凋亡增加；② 血糖波动能加剧缺血缺氧介导心肌细胞损伤和凋亡；③ JAK2/STAT3信号通路参与了血糖波动状态下缺血缺氧介导心肌细胞损伤；④ 益气养阴活血中药（PF、TMP和PQS）均能不同程度减轻血糖波动加重缺血缺氧介导心肌细胞损伤，以PF作用显著，且与调控JAK2/STAT3信号通路有关。体内复制2型糖尿病合并AMI及冠脉微血栓大鼠血糖波动复合模型，从脂质代谢、血栓形成、心肌梗死面积、心室重构以及JAK2/STAT3信号通路方面，应用PQS、TMP、PF和通路抑制剂AG490干预发现：① 血糖波动能加重2型糖尿病合并急性心肌梗死模型大鼠的脂质代谢异常、凝血功能及纤溶系统紊乱、心肌梗死面积增加、心室重构；② JAK2/STAT3信号通路参与了血糖波动状态下2型糖尿病合并急性心肌梗死模型大鼠血栓形成和心室重构；③ 益气养阴活血中药均能不同程度改善血糖波动介导2型糖尿病合并急性心梗死大鼠的上述生物学效应，以PF作用显著，且与调控JAK2/STAT3信号通路有关。该研究的开展对临床进行AMI后血糖稳态调控提供实验依据，促进益气养阴活血中药在急性冠脉病变防治中的应用。