我们前期临床研究发现急性心肌梗死患者PCI术后sRAGE增加与心功能改善呈正相关，实验发现sRAGE通过抑制心肌细胞凋亡拮抗I/R损伤，并证实sRAGE可通过增加UPS活性发挥作用。但sRAGE通过UPS抑制I/R损伤机制尚不明确。传统认为sRAGE阻断RAGE起作用,而其非RAGE途径还.不清楚。有研究表明sRAGE促进IFN-γ分泌，另有报道IFN-γ激活STAT1，而STAT1和STAT3增加UPS亚基表达。我们预实验发现sRAGE增加STAT3表达。据此，本研究拟在前期基础上利用RAGE基因敲除小鼠和心肌细胞I/R模型，应用生物化学和分子生物学等方法，明确sRAGE心脏保护作.用的具体信号途径，阐明sRAGE通过IFN-γ/STAT激活UPS抑制I/R心肌细胞凋亡的分子生物学机制。所获成果将丰富人们对sRAGE心脏保护作用机制的认识，并将为临床防治心肌I/R损伤提供有效的干预措施。

The treatment and prognosis of coronary heart disease is restricted by ischemia/reperfusion(I/R) injury. It’s important to explore the treatment strategies for I/R. The endogenous protective substances are involved in reducing I/R injury. From our previous projects, we have found a positive correlation between increasing of sRAGE after PCI for acute myocardial infarction and improving of heart function in clinical research, and sRAGE could alleviate I/R injury through inhibiting cardiomyocytes apoptosis in the animal study. The effect of sRAGE inhibition on I/R-induced apoptosis through increasing the activity of the ubiquitin-proteasome system(UPS) in vivo. However, the mechanism of sRAGE inhibiting I/R-induced apoptosis via UPS is unclear. Other study has showed that sRAGE can promote the secretion of IFN-γ, and another research have demonstrated that IFN-γ increases the subunit expression of UPS by activating STAT1. The previous pilot study has shown that sRAGE could increase expression of STAT. This project will use RAGE gene knockout mice to simulate model, left anterior descending artery occlusion induced I/R in vitro as well as ischemic buffer in isloated myocytes induced I/R in vivo. Markers will be detected including heart fuction, myocardial infarct size, cardiomyocytes apoptosis; the activity and subunit expression of UPS; the gene and protein experssion of IFN-γ, STAT1 and STAT3. The signaling pathways for sRAGE cardioprotective, and the molecular biological mechanism of sRAGE induced reduction on apoptosis through increasing the activity and expression of UPS will be systematically explored by using the techniques of biochemistry and molecular biology. Achievements of this research will enrich our understanding of sRAGE cardioprotective involved in I/R injury, and provide effective intervention for prevention and treatment of myocardium I/R injury.