RTEF-1通过Edg-1途径保护脂质负荷所致的血管内皮屏障损伤

Injured endothelial barrier is a hallmark in the early stage of athrosclerosis.It is important to discover potential protection factor of endothelial barrier for prevention and treatment of atherosclerosis.Related Transcriptional Enhancer Factor-1 (RTEF-1) play a key role in embryo development and has been suggested to take part in several pathophysiological process through regulating target genes. In our pretreatment experiments,it revealed that RTEF-1 took part in decreasing endothelial permeabiliy and inducing Endothelial differentiation gene-1(Edg-1) gene expression,which was an important actor in endothelial barrier enhancement. We hypothesesed that RTEF-1 might participate in enhancing endothelial barrier by stimulating Edg-1 ligand S1P synthesis,regulating Edg-1 function and activating post Edg-1 signal transduction.RTEF-1 over-expressing and RTEF-1 knockdown by its siRNA in human umbilical vein endothelial cell were conducted as cell models. Endothelial specific over-expression and knockout of RTEF-1 were used as animal models. Endothelial barrier effective molecules were detected before and after treatments of Edg-1 agonist,Edg-1 antagonist,different inhibitors of cellular signal transduction pathways with lipid loading by ox-LDL or high fat diet.It will be helpful to discover potential gene target drugs in atherosclerosis prevention and treatment.

血管内皮损伤是动脉粥样硬化（As）发生的始动环节，研究内皮屏障的保护因子对于As防治具有重要意义。RTEF-1是胚胎发育的关键基因，它作为转录调控因子通过对靶基因的调节参与诸多病理生理过程。我们的预实验发现RTEF-1具有降低血管内皮通透性、正性调控Edg-1基因表达的作用，而后者在内皮屏障功能中发挥着重要作用。因此我们推测RTEF-1可能通过干预Edg-1的配体生成、受体功能及受体后信号途径激活参与血管内皮屏障的效应分子发挥其保护作用。本课题以过表达RTEF-1及RTEF-1 siRNA作用的人脐静脉内皮细胞为细胞模型，ox-LDL进行脂质负荷诱导内皮细胞损伤，给予Edg-1激动剂、阻滞剂、不同信号通路抑制剂进行干预，观察下游效应分子的改变，研究RTEF-1的内皮屏障保护机制。将为开发靶向血管内皮保护药物防治As进行有益探索。

血管内皮损伤是动脉粥样硬化发生的始动环节，研究内皮屏障的保护因子对于动脉粥样硬化防治具有重要意义。RTEF-1是胚胎发育的关键基因，它作为转录调控因子通过对靶基因的调节参与诸多病理生理过程，但是RTEF-1是否参与内皮屏障的保护目前尚未明确。本课题以过表达RTEF-1及RTEF-1 siRNA作用的人脐静脉内皮细胞为细胞模型，ox-LDL进行脂质负荷诱导内皮损伤，观察细胞通透性改变及维持细胞屏障的重要效应分子的改变，结果发现RTEF-1基因有助于维持内皮屏障的完整性，其保护机制与调控细胞屏障的效应分子如Edg-1，SPHK1，SPHK2，CLDN3，CLDN4及CX43等有关。揭示RTEF-1的内皮保护作用将为开发靶向血管内皮保护药物防治动脉粥样硬化奠定理论基础。