内皮素-1信号通路致糖尿病心肌纤维化的分子机制研究

The prevalence of diabetes has increased significantly in recent decades and is now reaching epidemic proportions in China. Diabetes can induce disorders of the myocardial structure and function. Among the complications, myocardial fibrosis and capillary lesions, which are the basis of diabetic cardiomyopathy, play the most important role in cardiac dysfunction. Although the abnormal expression of endothelin system was confirmed to be related with diabetic myocardial fibrosis, the reciprocal interaction of growth factors and ET-1 in the progression of fibrosis is not clear. In the current study, C57BL/6 mice were used to made streptozotocin induced diabetic model. Western blotting, speckle tracking imaging, 18F-FDG PET/CT myocardial perfusion imaging, picric acid Sirius red staining, and cell culture techniques were used, according to the model of diabetic mice myocardium in vivo and myocardial cells cultured in vitro, giving the endothelin receptor antagonist (bosentan) intervention of ET receptor and ET-1 expression, and to explore the mechanism of ET-1 and its antagonist on myocardial fibrosis, to further clarify the relationship between the endothelin system and diabetic myocardial fibrosis. The aim of this study was to elucidate the mechanism of endothelin receptor antagonist on myocardial fibrosis and cardiac insufficiency. To clarify the above mentioned hypothesis will provide novel approach and experimental basis to cure diabetic myocardial fibrosis.

糖尿病在我国发病率逐年攀升，可导致心肌结构功能紊乱及心肌纤维化等糖尿病心脏并发症、心功能不全，预后严重不良。糖尿病患者血浆中ET-1含量升高，我们前期研究发现内皮素（ET）系统的异常表达与糖尿病心肌纤维化的形成密切相关，但具体机制及干预尚不明确。本课题通过链脲佐菌素诱导建立糖尿病心肌病小鼠模型，采用免疫印迹法、超声斑点追踪成像技术、18F-FDG PET/CT心肌灌注显像、苦味酸-天狼星红偏振光法和细胞培养等技术，针对糖尿病小鼠心肌组织及高糖环境下体外培养的心肌细胞，给予内皮素受体拮抗剂干预ET受体以及ET-1的表达，从动物整体水平和分子细胞水平探讨ET-1及其拮抗剂对心肌纤维化的作用机制，明确内皮素系统与糖尿病心肌纤维化之间的关系：ET-1是导致糖尿病心肌纤维化的核心信号通路，阐明内皮素受体拮抗剂对改善心肌纤维化、进而改善心功能不全的机理，为防治该病提供重要的理论及实验依据和治疗新思路。

糖尿病在我国发病率逐年攀升，可导致心肌结构功能紊乱及心肌纤维化等糖尿病心脏并发.症、心功能不全，预后严重不良。糖尿病患者血浆中ET-1含量升高，我们前期研究发现内皮素.（ET）系统的异常表达与糖尿病心肌纤维化的形成密切相关，但具体机制及干预尚不明确。本.课题通过链脲佐菌素诱导建立糖尿病心肌病小鼠模型，采用免疫印迹法、超声斑点追踪成像技.术、18F-FDG PET/CT心肌灌注显像、苦味酸-天狼星红偏振光法和细胞培养等技术，针对糖尿.病小鼠心肌组织及高糖环境下体外培养的心肌细胞，给予内皮素受体拮抗剂干预ET受体以及ET.-1的表达，从动物整体水平和分子细胞水平探讨ET-1及其拮抗剂对心肌纤维化的作用机制，明.确内皮素系统与糖尿病心肌纤维化之间的关系：ET-1是导致糖尿病心肌纤维化的核心信号通路.，阐明内皮素受体拮抗剂对改善心肌纤维化、进而改善心功能不全的机理，为防治该病提供重.要的理论及实验依据和治疗新思路。