Department of Cardiology, Wuhan General Hospital of PLA, Wuhan 430070, China.
Clinic Center, China Life Health Industry Group, Shenzhen 515000, China.
Cell Biol Int. 2018 Nov;42(11):1492-1502. doi: 10.1002/cbin.10991. Epub 2018 Jul 8.
Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that involves in numerous pathophysiological processes. Endothelial progenitor cells (EPCs) play a crucial role in endothelial repair and tumor angiogenesis. The aim of study was to determine the effects of S1P on proliferation and anti-apoptosis of EPCs and their signaling pathways. In this study, we showed that S1P, SEW2871 (a selective S1P receptor 1 (S1PR1) agonist), or CYM5541 (a selective S1P receptor 3 (S1PR3) allosteric agonist promotes the proliferation and attenuates apoptosis of bone marrow (BM)-derived EPCs. Futhermore, it was showed that S1P could promote EPCs proliferation, which could be significantly inhibited by pretreatment with CAY10444 (an S1PR3 antagonist), VPC23019 (a selective S1PR(1)/S1PR(3) antagonist), or LY294002 (a PI3K inhibitor). Moveover, we discovered that S1P could significantly attenuate H O -induced apoptosis and activation of caspase-3 in vitro, while W146 (an S1PR1 antagonist), VPC23019, or LY294002 could significantly increase the activation of caspase-3 and subsequent augmented apoptosis. Our results indicated that the protective effect of S1P is mediated by activating the PI3K/Akt pathway. In addition, S1P promotion of EPCs proliferation was observed to be mainly mediated through S1PR3 and attenuation of EPCs apoptosis induced by H O was mainly mediated through S1PR1; both of these effects are mediated by activating the PI3K/Akt pathway, which provides potentially useful therapeutic targets for coronary artery disease, diabetes mellitus, and cancer treatment.
鞘氨醇-1-磷酸（S1P）是一种生物活性溶血磷脂，参与多种病理生理过程。内皮祖细胞（EPCs）在血管内皮修复和肿瘤血管生成中起着至关重要的作用。本研究旨在探讨 S1P 对 EPCs 增殖和抗凋亡的作用及其信号通路。本研究表明，S1P、SEW2871（一种选择性 S1P 受体 1（S1PR1）激动剂）或 CYM5541（一种选择性 S1P 受体 3（S1PR3）别构激动剂）均可促进骨髓（BM）来源的 EPCs 的增殖并抑制其凋亡。此外，研究表明 S1P 可促进 EPCs 增殖，而 S1PR3 拮抗剂 CAY10444、选择性 S1PR1/S1PR3 拮抗剂 VPC23019 或 PI3K 抑制剂 LY294002 预处理可显著抑制 S1P 诱导的 EPCs 增殖。此外，我们发现 S1P 可显著减轻 H2O2 诱导的 EPCs 凋亡和 caspase-3 激活，而 S1PR1 拮抗剂 W146、VPC23019 或 LY294002 可显著增加 caspase-3 的激活，随后促进细胞凋亡。结果表明，S1P 的保护作用是通过激活 PI3K/Akt 通路介导的。此外，S1P 促进 EPCs 增殖主要通过 S1PR3 介导，减轻 H2O2 诱导的 EPCs 凋亡主要通过 S1PR1 介导，这两种作用均通过激活 PI3K/Akt 通路介导，为冠心病、糖尿病和癌症治疗提供了潜在的治疗靶点。
