从lncRNA-PART1调控FoxO1自噬途径探讨运脾活血散结方改善糖尿病心肌损伤的作用机制

Diabetic cardiomyopathy (DCM) is a specific cardiomyopathy characterized by abnormal myocardial structure and diastolic dysfunction. So far, there is no effective treatment. The occurrence of T2DM is accompanied by the formation of myocardial injury. Based on the idea of “preventing measure taken after the occurrence of disease”, we realize that the core TCM pathogenesis of DCM is “dysfunction of the spleen in transport and phlegm and blood stasis”. The previous study of the research group showed that Yunpi Huoxue Sanjie Recipe can significantly improve the IR of T2DM patients; it can improve the myocardial injury by means of the autophagy regulator FoxO1 expression in DCM rats. We speculate that autophagy clearance the “phlegm and blood stasis” binding with cell tightly, that may be a microscopic manifestation of the method of activating spleen, activating blood and dissipating binds. Therefore, we assume that Yunpi Huoxue Sanjie Recipe can activate the FoxO1 autophagy pathway by down-regulating lncRNA PART1, improve the level of myocardial autophagy in DCM rats, and improve myocardial injury. In this project, we intend to establish rat animal and cardiomyocyte models, and use bioinformatics, lncRNA chip, siRNA interference and other techniques to observe the effects of Yunpi Huoxue Sanjie Recipe on lncRNA and autophagy pathway-related molecules. To explore the possible targets for improving myocardial injury in DCM rats, and provide scientific basis for the advantages of traditional Chinese medicine in preventing and treating DCM based on the idea of “preventing measure taken after the occurrence of disease”.

糖尿病心肌病（DCM）是以心肌结构和心脏舒张功能异常为主要表现的特异性心肌病，迄今尚无有效的治疗方法。T2DM发生即伴随心肌损伤的形成，基于“既病防变”思想，我们认为DCM的中医核心病机为“脾失健运，痰瘀互结”。课题组前期研究表明，运脾活血散结方可明显改善T2DM患者IR状况；可提高DCM大鼠心肌自噬调控因子FoxO1的表达水平发挥心肌保护作用。我们推测自噬清除与细胞“结”为一体的“痰瘀”可能是运脾活血散结法的一种微观体现。故提出假说：运脾活血散结方可通过下调lncRNA PART1激活FoxO1自噬途径，提高DCM大鼠心肌自噬水平，改善心肌损伤。本项目拟建立大鼠动物和心肌细胞模型，应用生物信息学、lncRNA芯片、siRNA干扰等技术，观察运脾活血散结方对lncRNA和自噬途径相关分子的影响，探讨其改善DCM大鼠心肌损伤的可能作用靶点，为中药发挥对T2DM的“既病防变”优势提供科学依据。

糖尿病心肌病（DCM）是以心肌结构和心脏舒张功能异常为主要表现的特异性心肌病，迄今尚无有效的治疗方法。T2DM发生即伴随心肌损伤的形成，基于“既病防变”思想，我们认为DCM的中医核心病机为“脾失健运，痰瘀互结”。课题组前期研究表明，运脾活血散结方可明显改善T2DM患者IR状况；可提高DCM大鼠心肌自噬调控因子FoxO1的表达水平发挥心肌保护作用。本课题在前期研究基础上，建立大鼠动物和心肌细胞模型，以运脾活血散结方为干预手段，采用生物信息学、siRNA干扰、免疫荧光染色、免疫印迹等技术，观察运脾活血散结方对lncRNA相关自噬途径相关分子的影响。结果发现活血散结方可通过PART1调控FoxO1自噬途径，上调FoxO1及自噬相关蛋白Atg7、Atg12、Beclin 1、LC3表达，下调FoxO1磷酸化水平和p62表达，提高心肌细胞自噬水平，发挥改善糖尿病心肌损伤的作用。部分阐明了依“脾失健运、痰瘀互结”立法的运脾活血散结方改善T2DM心肌损伤的作用机制，为中药发挥对T2DM的“既病防变”优势提供科学依据。