铁调素在2型糖尿病心肌病发生发展中的作用及机制研究

Previous study showed that iron metabolism is closely related to diabetes. Iron overload could increase the production of reactive oxygen species (ROS), which could significantly promote diabetic cardiomyopathy (DCM). Hepcidin (Hep), as an important signal substance for promoting intracellular iron deposition, has become a hot topic in recent years. However，there is still no report about the relationship between Hep and DCM. In our preliminary work, we found that the expression of Hep greatly increased in the left ventricular myocardium of type 2 DCM db/db mice and the Hep’s expression level is somewhat relevant to the heart function. Meanwhile, we found that Hep, induced by high glucose in the cardiomyocytes and the cardiac fibroblasts could up-regulate the iron level in the two cells. Accordingly, we put forward the hypothesis that in the development of type 2 DCM，high expressed Hep promotes cardiomyocyte apoptosis and collagen synthesis in cardiac fibroblasts by effecting on the intracellular iron metabolism, and then accelerates the DCM process. Therefore, by focusing on Hep study, this project designed the in vivo study and in vitro study to throughly explore Hep’s role in the cardiomyocyte apoptosis and myocardial interstitial fibrosis as well as its relationship with iron metabolism and oxidative stress, with the help of the techniques of molecular biology and echocardiography diagrams. By gene over-expression and silencing techniques, we will study the effect of Hep on the cardiac structure and function in a type 2 DCM mice model and the relevant molecular mechanism. This proposed project will enrich our understanding of Hep’s biological function, provide a new target and a new solution to the prevention and treatment of diabetic cardiomyopathy, and thus has great theoretical significance and practical value.

机体铁超载与糖尿病关系密切，过量铁在心脏沉积通过介导氧化应激反应促进糖尿病心肌病（DCM）的发展。铁调素（Hep）是体内铁代谢的重要调控分子，具有促进细胞内铁沉积的作用，但关于Hep与DCM的关系，迄今尚无报道。前期研究显示，2型DCM db/db小鼠左室心肌Hep高表达且表达水平与心脏功能有一定相关性；高糖刺激心肌细胞和心肌成纤维细胞诱导Hep表达，而后者作用于两种细胞后上调细胞内铁水平。据此，我们推测，在2型DCM发展过程中，心脏Hep表达升高，通过对细胞铁代谢和氧化应激的影响而促进心肌细胞凋亡和心肌间质纤维化，加速DCM进程。本课题拟以Hep为研究靶点，利用分子生物学、超声心动图等技术，深入探讨Hep在心肌细胞凋亡、心肌成纤维细胞胶原合成中的作用及与铁代谢和氧化应激的关系，并通过Hep基因干预，阐明其对2型DCM心脏结构和功能的影响及分子机制，为糖尿病心肌病防治提供新的靶点和思路。

糖尿病心肌病（diabetic cardiomyopathy，DCM）是糖尿病的重要并发症，也是糖尿病患者高心力衰竭发生率和高死亡率的主要原因。DCM的主要病理变化包括心肌细胞凋亡和心肌间质纤维化两个方面，但两者的发生和调控机制尚未阐明，因此缺乏有效的干预措施。本项目应用细胞生物学、分子生物学、病理组织学、及超声影像学技术，以心肌成纤维细胞和2型糖尿病小鼠为研究对象，探讨铁调素（Hepcidin，Hep）在 DCM 发生发展中的作用。结果显示：（1）高糖刺激引起心肌成纤维细胞Hep表达升高，进而降低膜铁转运蛋白（Ferroportin1，Fpn1）水平，导致细胞内铁沉积增多，铁蛋白水平升高；（2）Hep促进高糖诱导的心肌成纤维细胞内铁沉积，增强铁介导的氧化应激损伤，显著升高Ⅰ、Ⅲ型胶原表达水平；（3）Hep基因沉默改善了2型糖尿病小鼠的胰岛素抵抗；（4）Hep基因沉默改善DCM心肌间质纤维化、减少心肌细胞凋亡，改善了左室舒张功能；