1-磷酸鞘氨醇受体信号通路在氧化应激致内皮细胞损伤中的作用与机制

Vascular endothelial injury is positively correlated with the morbidity and mortality of cardiovascular disease. Oxidative stress is one of the main factors resulting in endothelial cell dysfunction and vascular endothelial injury. Previous studies have shown that sphingosine-1-phosphate (S1P) regulates an array of biological activities in endothelial cells mediated by sphingosine-1-phosphate receptors (S1PRs). Our studies have shown that the imbalance of S1PR1/S1PR2 expression in endothelia cells with high glucose treatment was associated with endothelia dysfunction. Therefore, based on the previous study, our aims of this project are: 1. to further determine the relationship between changes of S1PR1/S1PR2 expression and its signaling pathways downstream in endothelial cells, and the endothelia dysfunction during the oxidative stress process. 2. to observe the effect of an imbalance of S1PR1/S1PR2 receptor on endothelia function by up-regulating S1PR1 receptor and blocking S1P2 receptor in endothelial cells during the oxidative stress process, thus revealing whether an imbalance of S1PR1/S1PR2 pathway mediates endothelia cell impairment. 3. to evaluate the effect of S1PR1/S1PR2 receptor signaling pathway on endothelia function by blocking some signal molecules correspondingly in endothelia cells during the oxidative stress process, thus clarifying the role of an imbalance of S1PR1/S1PR2 signaling in endothelia dysfunction induced by oxidative stress and its mechanism. Therefore, understanding the molecular mechanisms of vascular endothelial cell dysfunction and endothelial injury induced by oxidative stress will be helpful in both prevention and treatment of cardiovascular disease.

内皮损伤是血管疾病发生的起始环节，而氧化应激是导致血管内皮损伤的主要因素之一；血液中1-磷酸鞘氨醇（S1P）可通过内皮细胞表面的1-磷酸鞘氨醇受体（S1PR）介导，激活细胞内不同信号通路而产生广泛的生物学效应。我们前期的研究通过分析内皮细胞S1PR表达与高糖诱导内皮细胞氧化应激损伤的关系；结果发现氧化应激致内皮细胞损伤过程中S1PR1表达显著降低和S1PR2表达明显升高，推测S1PR信号通路可能参与氧化应激致内皮细胞的损伤作用。因此，本项目拟采用氧化应激的内皮细胞模型、糖尿病和高脂血症小鼠模型，通过调控S1PR1/S1PR2的表达，分析对内皮细胞的功能变化；以及通过激活或阻断氧化应激致内皮细胞损伤过程中S1PR下游信号通路中的相应靶分子，评价其对内皮细胞的功能影响；以探讨S1PR信号通路在氧化应激致内皮细胞损伤中的作用与机制，为预防和治疗氧化应激所致血管疾病提供侯选靶标和理论依据。

内皮损伤是血管疾病发生的起始环节，而氧化应激是导致血管内皮损伤的主要因素之一；血液中1-磷酸鞘氨醇可通过内皮细胞表面的1-磷酸鞘氨醇受体（S1PR）介导，激活细胞内不同信号通路而产生广泛的生物学效应。我们的预实验通过分析内皮细胞S1PR表达与高糖诱导内皮细胞氧化应激损伤的关系；发现了氧化应激致内皮细胞损伤过程中S1PR2表达明显升高，推测S1PR2信号通路可能参与氧化应激致内皮细胞的损伤作用。.本项目采用氧化应激的内皮细胞模型、糖尿病小鼠模型，通过调控S1PR2的表达，分析对内皮细胞的功能变化；以及通过激活或阻断氧化应激致内皮细胞损伤过程中S1PR2下游信号通路中的相应靶分子，评价其对内皮细胞的功能影响；探讨S1PR2信号通路在氧化应激致内皮细胞损伤中的作用与机制。结果发现：高糖可上调肾小球内皮细胞（HRGECs）中S1PR2 表达，抑制S1PR2 可改善由高糖诱导的HRGECs 线粒体分裂增加、ATP 生成减少、ROS 产生增多和钙超载以及单层细胞屏障功能下降、凋亡率增加和迁移能力下降。抑制HRGECs的S1PR2 可降低由高糖介导的RhoA、 ROCK1及DRP1 表达增高，进一步抑制ROCK1 也可改善由高糖诱导的HRGECs 线粒体分裂增加、ATP 生成减少、ROS 产生增多和钙超载以及单层细胞屏障功能下降、凋亡率增加及迁移能力下降。.完成了项目计划任务指标，达到了预期目标，揭示了S1PR2介导的信号通路在高糖所致内皮细胞氧化应激中的作用和机制；明确了线粒体钙单向转运体对高糖诱导内皮细胞功能障碍的作用；阐明了维格列汀通过抑制线粒体分裂改善高糖诱导内皮细胞中线粒体功能障碍机制；为预防和治疗氧化应激所致血管疾病提供侯选靶标和理论依据。发表SCI 论文8 篇。培养2名博士毕业，2名硕士毕业。

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