心肌纤维化是糖尿病心肌病（DCM）的重要病理基础。ADMA为NOS抑制物，由DDAH1代谢。DDAH1/ADMA在糖尿病血管病变发展中起重要作用，但是否参与DCM心肌纤维化尚不清楚。LncRNAs和mRNA可通过竞争结合相同miRNA，实现RNA与RNA相互调控。心肌纤维化时miR-21上调，敲低LncRNA-GAS5能上调miR-21，DDAH1可能是miR-21的靶基因。预实验发现，糖尿病大鼠心肌组织DDAH1和LncRNA-GAS5水平下调，miR-21上调，伴随ADMA和内皮细胞间质转化（EndMT）明显。本项目拟探讨：心肌微血管EndMT在DCM心肌纤维化中的作用；DDAH1/ADMA在EndMT和DCM心肌纤维化中的作用及信号途径；LncRNA-GAS5和miR-21在DCM心肌纤维化中的作用及二者的相互关系；LncRNA-GAS5/miR-21调控DDAH1的表达作用及机制。

Diabetic cardiomyopathy (DCM), one of the most common microvascular complications, is characterized by cardiac fibrosis. Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is mainly metabolized by dimethylarginine dimethylaminohydrolase 1 (DDAH1). DDAH1/ADMA pathway plays important roles in the development of diabetic vascular complications. However, whether DDAH1/ADMA pathway is involved in cardiac fibrosis of DCM remains unclear. Non encoding RNAs include small non-encoding RNAs (miRNAs) and long non-encoding RNAs (LncRNAs). LncRNAs and mRNAs modulate each other's abundance by using miRNAs response elements to compete for the binding site of microRNA. It has been reported that miR-21 is elevated in cardiac fibrosis, and siRNA LncRNA-GAS5 increases the levels of miR-21. Bioinformatics analysis shows that DDAH1 may be the target gene of miR-21. Our pilot study showed the decrease in DDAH1 and LncRNA-GAS5, and the increase in miR-21, ADMA and endothelial-mesenchymal transition (EndMT) related protein (such as alpha-SMA and Vimentin) in myocardium of STZ-induced diabetic rat. Based on above results, in the present study we will be planning to explore: the role of cardiac microvascular EndMT in cardiac fibrosis of DCM; the potential role of DDAH1/ADMA pathway in cardiac fibrosis of DCM and the downstream signaling pathway of DDAH1/ADMA in mediating cardiac microvascular EndMT (focusing on TGF-beta1/Smad/Snail or TGF-beta1/non-smad ); the role of LncRNA-GAS5 and miR-21 in cardiac fibrosis of DCM and the potential relationship among DDAH1, LncRNA-GAS5 and miR-21. This study will contribute to the understanding of the pathogenesis of cardiac fibrosis in DCM, and provide novel strategies to seek for the new targets and new drugs responsible for cardiac fibrosis of DCM.