川芎嗪调控内皮-血小板-炎症相关microRNA干预冠脉微循环障碍的效应和机理研究

Improving coronary microvascular dysfunction (CMD) is of great clinical significance for reducing cardiovascular events. The coronary microvascular thrombosis caused by endothelium-platelet-inflammation network disorder is an important pathogenesis of CMD. Numerous studies have shown that microRNA (miRNA) play important roles in the structure and function of coronary microcirculation via regulating the expression of protein involved in vascular endothelial dysfunction, platelet activation and inflammation. According to literatures, ligustrazine could improve endothelial function and exert antiplatelet and anti-inflammatory effects. However, the regulatory effect and mechanism of ligustrazine on CMD remain unclear. Based on our previous research, we establish coronary microthrombus animal model to simulate the occurrence of CMD and decteted the differently expressed miRNAs, then verify the regulatory effect of ligustrazine on CMD and explore the molecular mechanism through the key miRNA-gene pathways involved in endothelium-platelet-inflammation network. The present study may provide experimental evidence and molecular targeting for clinical application of ligustrazine in prevention and treatment of coronary heart disease.

改善冠脉微循环障碍对减少心血管事件的发生具有重要的临床意义。内皮-血小板-炎症网络调控异常导致的冠状动脉微血管栓塞是冠脉微循环障碍的一个重要发病机制。有证据显示，microRNA（miRNA）参与调节血管内皮功能异常、血小板活化及炎症相关的多种重要蛋白表达，对冠脉微循环的结构和功能有着重要调控作用。以往研究表明，川芎嗪有保护血管内皮、抗血小板和抗炎的作用，但其干预冠脉微循环障碍的效应和分子机理尚不明确。本课题在前期研究工作的基础上，应用冠脉微血栓动物模型模拟冠脉微循环障碍，以冠脉微循环障碍状态下差异表达的miRNA为研究切入点，探索在内皮-血小板-炎症网络中起关键调控作用的目标miRNA-靶基因通路，证实活血化瘀中药成分川芎嗪对冠脉微循环障碍的干预效应，并从目标miRNA-靶基因通路阐明其分子机理，为川芎嗪防治冠心病的临床转化应用提供实验依据。

内皮-血小板-炎症网络调控异常导致的冠状动脉微血管栓塞是冠脉微循环障碍的一个重要发病机制，microRNAs（miRNAs）可能在其中发挥重要调控作用。前期研究表明，活血化瘀中药有效成分川芎嗪具有抑制冠脉局部微血栓形成、改善冠脉微循环障碍的作用，但其分子机制尚不明确。针对这一问题，本项目应用冠脉微血栓大鼠模型模拟冠脉微循环障碍，探索与冠脉微循环障碍相关的、在内皮-血小板-炎症网络中发挥重要调控作用的miRNAs/靶基因，并以此为切入点探讨川芎嗪调控改善冠脉微循环障碍的分子机制，为川芎嗪防治冠心病的临床转化应用提供实验依据。本研究发现，高表达的miR-34a-5p可通过直接靶向抑制Sirt1表达促进冠脉微循环障碍的发生发展。川芎嗪可通过改善内皮功能、抗血小板、抗炎进而抑制冠脉微血栓形成、改善冠脉微循环障碍的作用，其机制可能与川芎嗪抑制miR-34a-5p表达、促进Sirt1 mRNA和蛋白表达进而增加eNOS表达、抑制NFκB激活的效应有关。