糖尿病血管内皮仿生微环境下多因素内皮损伤及硒蛋白S抗氧化保护分子机制

内皮功能紊乱是糖尿病大血管并发症的始动环节，与血管微环境变化密切相关。针对其细胞水平研究多采用与机体内环境差别较大的传统细胞培养和单因素干预方式，而糖尿病患者常同时合并多种心血管危险因素并缺少有效内皮保护策略。我们前期研究发现硒蛋白S（SelS）可通过抗氧化保护人脐静脉内皮细胞并与蛋白激酶Cα（PKCα）相关。本课题拟在此基础上以微流控芯片作为微环境构建平台，将调整培养液成分（糖及氧化型低密度脂蛋白浓度）和调控压力刺激有机结合，首次在糖尿病血管内皮仿生微环境下观察高糖、高脂及高压复合因素对内皮细胞功能的影响，并对SelS抵抗多因素氧化应激引起的内皮损伤及可能涉及的PKCα/磷脂酰肌醇3-激酶（PI3-K）信号通路进行研究。成果有助于为内皮保护基础研究提供全新仿生技术平台，深入阐释糖尿病大血管并发症发病机制，并为SelS作为靶向抗氧化防治糖尿病大血管并发症的新药研发提供可靠实验依据。

Endothelial dysfunction is an initiating key step for diabetic macrovascular complications, and it is closely related to the hemodynamic microenvironment in vivo. A single factor stimulus combined with conventional cell culture in vitro in static condition rather than dynamic microenvironment is currently the major approach to investigate endothelial dysfunction in cytological study. However, diabetic patients usually coexist with other cardiovascular risk factors, and the more powerful targeting strategy for protecting endothelium is still limited. In our previous research, we found that selenoprotein S (SelS) could increase human umbilical vein endothelial cells (HUVECs) resistance to oxidative stress associated with protein kinase C α (PKCα). Therefore, in this study, we plan to construct a diabetic vascular endothelium microenvironment mimicking hyperglycemia, hyperlipidemia, and hypertension on the basis of microfluidics through modulating the concentration of medium glucose and oxidized low density lipoproteins (ox-LDL) integrated with different pressure (stretching) stimuli. More importantly, we intend to delve into the mechanism of multifactorial endothelial injury and antioxidant protection of SelS through the probable PKCα/phosphatidy linositol 3-kinase (PI3-K) signaling pathway. Our results will offer a promising and biomimetic platform for investigation on endothelial protection. Moreover, this study will not only elucidate the pathological mechanism of diabetic macrovascular complications but also provide solid experimental evidence for promoting the development of SelS as a newly targeting antioxidant drug to treat diabetic macrovascular complications.