基于LncRNA H19与自噬、炎症信号通路揭示升陷祛瘀中药治疗糖尿病心肌病疗效靶点及其信号机制研究

Diabetes cardiomyopathy is one of the major complications of diabetes, which is associated with the high hospitalization and disablility rates of patients with diabetes, causing a heavy burden of our society and economy. Autophagy and inflammatory reaction play a crucial role in the development and progression of diabetic cardiomyopathy. Further study of it can help illustrate mechanisms of the pathogenesis of diabetes cardiomyopathy and provide objective support for its treatment. Our previous researches have found that myocardial cell inflammation, mTOR-related signal pathway disorders and myocardial autophagy imbalance led to myocardial cell damage and decreased cardiac function under high glucose state. Based on the ‘removing blood stasis by escalation’ theory of Traditional Chinese medicine, ShengJieTongYu decoction has a significant effect on preventing and treating myocardial diseases. In this study, we plan to establish a model of diabetic rats with myocardial injury and systematically validate the role of LncRNA H19 / mTOR / NF-κB signaling pathway and autophagy in DCM myocardial injury. In vitro experiments, we adopted pathways-related regulating factors to reveal the specific changes in th signaling network and find the accurate target site of ShengJieTongYu Decoction, illustrating the the functioning sites of ShengJieTongYu decoction, and provide scientific evidence as well as objective basis for treating DCM.

糖尿病心肌病是糖尿病的主要并发症之一，与糖尿病患者的高致残率和高死亡率密切相关，对社会和经济带来沉重负担。炎症反应和自噬在糖尿病心肌病发生发展过程中起关键作用，探索炎症反应和自噬信号通路有助于我们发现糖尿病心肌病的发病机制，为治疗这一疾病提供客观依据。我们前期研究工作发现，高糖状态下心肌细胞炎症及mTOR相关信号通路调节紊乱，心肌细胞自噬平衡失调，导致心肌细胞损伤，心功能下降。而基于中医升陷祛瘀理论而创立的升陷祛瘀汤对心肌病变有较好的防治作用。据此，本研究拟通过建立糖尿病心肌损伤大鼠模型，系统验证LncRNA H19/mTOR/NF-κB信号通路网络和自噬在DCM心肌损伤中的作用，体外实验采用通路关键调节因子，揭示上述信号通路网络的特异性改变，明确升解通瘀汤的治疗靶点，揭示升解通瘀汤的心肌保护作用的机理，为临床治疗糖尿病心肌病提供科学依据及客观指标。

糖尿病心肌病是糖尿病的主要并发症之一，对社会和经济带来沉重负担，故而迫切解决此问题。自噬在糖尿病心肌病发生发展过程中起关键作用，高糖状态下心肌细胞炎症及mTOR相关信号通路调节紊乱，心肌细胞自噬平衡失调，导致心肌细胞损伤，心功能下降。本研究通过建立糖尿病心肌损伤大鼠模型，系统验证LncRNA H19/ mTOR/ NF-κB信号通路网络和自噬在DCM心肌损伤中的作用。本次实验发现：升解通瘀汤通过调节LncRNA H19的作用后，激活PI3K/Akt和mTOR通路后抑制自噬反应进而改善了糖尿病心肌的存活率，抑制了凋亡反应，进而总体改善了心功能。本实验通过小动物超声，证实了升解通瘀汤具有改善糖尿病心肌病的作用；通过病理学，电镜观察等形态学手段明确了该药物在细胞及亚细胞器层面对心肌具有有保护作用；通过免疫荧光和western-blot及体外实验加纠正实验的方法也验证了升解通瘀汤与H19，PI3K/Akt，自噬的关系。本实验从体内/动物实验到体外/心肌细胞实验及心肌细胞亚细胞器这三个层面证实了升解通瘀汤对糖尿病心肌病自噬的抑制作用进而改善心功能，为进一步阐述本药物乃至中医药对心肌相关疾病的治疗提供了新思路，阐述了新机理，具有重要的社会和医疗价值。

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