冠脉钙化是一种复杂的病理生理过程，也是糖尿病冠心病患者介入治疗失败的重要原因。有研究显示转骨表型EPC可能与冠脉钙化有关，而HMGB-1作为一种损伤相关分子模式，可以促进多种糖尿病心血管并发症的发生发展。本课题组已证实，糖尿病时氧化应激介导的正反馈可以促进HMGB-1的表达及分泌。预实验中，我们发现糖尿病大鼠骨髓来源EPC中内质网应激相关蛋白表达升高。故申请者提出“HMGB-1通过内质网应激促进EPC转骨化是糖尿病冠脉钙化的重要机制”这一假说。为此，本课题拟用糖尿病大鼠动物模型在体研究HMGB-1、内质网应激、转骨表型EPC之间的关系，进一步在细胞实验中通过RNA干扰、免疫荧光等手段阐明内质网应激相关的PERK/eIF2α/ATF4通路在HMGB-1诱导EPC成骨化中的作用。此研究将为糖尿病冠脉钙化的防治提供新的理论基础及诊疗靶点。

Coronary artery calcification, a complex pathophysiological process, is a leading failure cause of the interventional therapy in diabetic patients with coronary heart disease. Growing evidence has shown the link between osteogenic endothelial progenitor cells (EPCs) and vascular calcification, and High mobility group box-1 (HMGB-1), a damage-associated molecular pattern, has been shown to promote diabetes related cardiovascular complications. Our previous studies have demonstrated that oxidative stress-mediated-positive feedback could induce the expression and release of HMGB-1 in diabetes. In addition, endoplasmic reticulum stress (ERS) related proteins have been reported to be higher in bone marrow derived EPCs from diabetic rats compared to control rats. Thus, we speculate that HMGB-1-induced osteogenic EPCs play an important role in diabetic vascular calcification. Here, in vivo experiments were performed to explore the relation between HMGB-1, ERS and osteogenic EPCs. Furthermore, in in vitro experiments, we will reveal the role of PERK/eIF2α/ATF4 pathway in HMGB-1-induced osteogenic EPCs using RNA interference, immunofluorescence and other methods. The present investigation will provide theoretic bases and therapeutic target for diabetic vascular calcification.