1-磷酸鞘氨醇在高糖诱导血管内皮细胞功能损伤中的作用

摘要

目的：探讨1-磷酸鞘氨醇（S1P）在高糖诱导血管内皮细胞功能损伤中的作用及其机制。方法：在高糖培养的人主动脉内皮细胞模型中，分别或同时给予S1P、鞘氨醇激酶1抑制剂和Akt抑制剂处理后，观察一氧化氮（NO）、粒细胞-内皮细胞黏附率、细胞间黏附分子1（ICAM-1）蛋白表达、内皮细胞迁移以及Akt／内皮型一氧化氮合酶（ eNOS）信号途径的改变。结果：S1P明显降低高糖诱导的内皮细胞培养上清液中NO含量，促进粒细胞与内皮细胞黏附，显著增加内皮细胞ICAM-1蛋白表达，抑制内皮细胞迁移和Akt／eNOS信号通路激活。鞘氨醇激酶1抑制剂减少S1P生成后上述内皮细胞功能指标得以明显改善，Akt／eNOS信号通路恢复激活。结论： S1P促进高糖培养的内皮细胞功能障碍的形成，可能与其抑制Akt／eNOS信号通路激活有关。抑制S1P生成有望成为减轻内皮细胞功能损伤的治疗策略之一。%AIM:To explore the role of sphingosine 1-phosphate (S1P) in the dysfunction of vascular endo-thelial cells exposed to high glucose.METHODS: In human aortic endothelial cells cultured under high-glucose ( 22 mmol/L glucose) medium, nitric oxide ( NO) level, polymorphonuclear neutrophil-endothelial cell adhesion rate, protein level of intercellular adhesion molecule-1 ( ICAM-1) , migration of endothelial cells and Akt/endothelial nitric oxide syn-thase ( eNOS) pathway activation were observed after S1P, sphingosine kinase-1 inhibitor and/or Akt inhibitor treatments. RESULTS:S1P decreased NO level, increased polymorphonuclear neutrophil adhesive rate, enhanced ICAM-1 protein level, and inhibited migration of endothelial cells and activation of Akt/eNOS pathway in endothelial cells cultured under high-glucose condition.Sphingosine kinase-1 inhibitor, which reduced S1P content, significantly improved the above endo-thelial cell function indexes and restored the activation of Akt/eNOS pathway.CONCLUSION: S1P promoted high glu-cose-induced dysfunction of endothelial cells probably by inhibiting the activation of Akt/eNOS signal pathway.Targeting S1P is expected to become one of potential treatment strategies to reduce endothelial cell dysfunction.