硒蛋白S的O-GlcNAc糖基化修饰对糖尿病血管内皮细胞炎症反应的影响

Endothelial cell dysfunction is the initial step for the macrovascular complicatants in diabetes. Diabetes-associated endothelial dysfunction addresses two risk factors: one is glucose metabolism-related, another is cardiovascular metabolism-related which includes inflammatory factors as the important role. Selenoprotein S is responsible for relieving oxidative stress, inflammatory injury and insulin resistance in diabetes as reported, but there is few report showing that post-translational modification of SelS plays role in endothelial dysfunction till now. Our preliminary results first showed the augmentation of O-GlaNAcylation of SelS in endothelial cells which were exposed to hyperglycemia and inflammation as stimuli. In addition, decreasing O-GlcNAcylation of SelS reduced the inflammatory response in endothelial cells significantly. Based on the above set of results, the way by which the O-GlcNAcylation of SelS modulates the diabetes-associated endothelial inflammatory response as well as the involvement of ROS/MAPK/NF-κB signaling pathway in the whole process would be further elucidated. Besides, the modification position of O-GlcNAcylated SelS would be confirmed. This study would amazingly contribute to intensively understanding the molecular mechanism by which SelS protects against diabetes-associated endothelial inflammatory response and dysfunction, and open up a new direction for the treatment of diabetic macrovasccular complictants.

内皮细胞功能紊乱是导致糖尿病大血管病变的始动环节。糖代谢紊乱与心血管代谢危险因素是糖尿病内皮细胞功能紊乱的两类危险因素，而炎症因子是影响心血管代谢的重要危险因素。硒蛋白S（selenoprotein S，SelS）具有保护内皮细胞氧化损伤、炎症反应等作用，但SelS翻译后修饰对内皮细胞功能紊乱作用的研究未有报道。本研究前期结果首次表明在高糖及TNF-α刺激下，内皮细胞SelS的O-GlcNAc糖基化修饰水平显著增高；下调SelS的O-GlcNAc修饰可显著缓解内皮细胞炎症反应。基于此，本项目拟深入阐释SelS的O-GlcNAc糖基化水平如何影响糖尿病内皮细胞炎症性反应，以及ROS/MAPK/NF-κB信号通路在此过程中的作用，并明确SelS发生O-GlcNAc修饰的位置。研究成果突破性探讨SelS抗击糖尿病内皮细胞炎症反应及功能紊乱的分子机制，为防治糖尿病大血管病变的新药研发开辟新路。

内皮细胞功能紊乱是导致糖尿病大血管病变的始动环节。糖代谢紊乱与心血管代谢危险因素是糖尿病内皮细胞功能紊乱的两类危险因素，而炎症因子是影响心血管代谢的重要危险因素。硒蛋白S（selenoprotein S，SelS）具有保护内皮细胞氧化损伤、炎症反应等作用，但SelS翻译后修饰对内皮细胞功能紊乱作用的研究未有报道。本研究结果表明在TNF-α刺激下，OGT通过与SelS结合介导内皮细胞SelS的O-GlcNAc糖基化修饰水平显著增高；同时，TNF-α可抑制SelS的磷酸化修饰；抑制SelS的O-GlcNAc修饰可逆转受到抑制的磷酸化修饰。另外，下调SelS的O-GlcNAc修饰可通过ROS、MAPK和NF-κB通路显著缓解内皮细胞炎症反应。研究成果从新的角度探讨SelS抗击内皮细胞炎症反应及功能紊乱的分子机制。