S1PR2 antagonist alleviates oxidative stress-enhanced brain endothelial permeability by attenuating p38 and Erk1/2-dependent cPLA2 phosphorylation
S1PR2 antagonist alleviates oxidative stress-enhanced brain endothelial permeability by attenuating p38 and Erk1/2-dependent cPLA2 phosphorylation
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DOI：
10.1016/j.cellsig.2018.09.019
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发表时间：
2019-01-01
影响因子：
4.8
通讯作者：
Li, Shengnan
中科院分区：
文献类型：
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作者：
Cao, Changchun;Dai, Li;Li, Shengnan
鞘氨醇-1-磷酸受体-2 （S1PR2）和胞质磷脂酶A(2) （cPLA(2)）都与实验性脑卒中中脑血管完整性的破坏有关。然而，在脑缺血诱导的内皮功能障碍中，S1PR2在诱导cPLA(2)磷酸化中的作用尚不清楚。本研究探讨S1PR2阻断对氧化应激诱导的脑血管内皮屏障损伤的影响，并探讨其可能的机制。在bEnd3细胞中，cPLA(2)抑制剂CAY10502和S1PR2拮抗剂JTE013能显著抑制过氧化氢（H2O2）诱导的细胞旁通透性和ZO-1定位的变化。除了p38，细胞外信号调节激酶（Erk） 1/2也是H2O2增加cPLA(2)磷酸化和内皮通透性所必需的。药理和遗传抑制S1PR2显著抑制其对H2O2的磷酸化。尤其是慢病毒介导的S1PR2的敲低抑制h2o2诱导的ZO-1再分布和细胞旁高通透性。在永久性大脑中动脉闭塞（pMCAO）小鼠模型中，我们发现JTE013预处理显著降低了Evans蓝染料（EBD）外渗，逆转了梗死半球VE-cadherin、occludin、claudin-5和CD31表达的下降。慢病毒介导的S1PR2敲低也能减轻EBD外渗。此外，JTE013预处理可减轻神经功能缺损、脑水肿和梗死体积。因此，我们的研究结果表明，JTE013对脑内皮屏障完整性的保护作用可能是通过抑制氧化应激下p38和erk1 /2依赖性的cPLA(2)磷酸化介导的。
Both sphingosine-1-phosphate receptor-2 (S1PR2) and cytosolic phospholipase A(2) (cPLA(2)) are implicated in the disruption of cerebrovascular integrity in experimental stroke. However, the role of S1PR2 in induction of cPLA(2) phosphorylation during cerebral ischemia-induced endothelial dysfunction remains unknown. This study investigated the effect of S1PR2 blockade on oxidative stress-induced cerebrovascular endothelial barrier impairment and explored the possible mechanisms. In bEnd3 cells, cPLA(2) inhibitor CAY10502 as well as S1PR2 antagonist JTE013 profoundly suppressed hydrogen peroxide (H2O2)-induced changes of paracellular permeability and ZO-1 localization. Besides p38, extracellular signal-regulated kinase (Erk) 1/2 is required for H2O2 increased cPLA(2) phosphorylation and endothelial permeability. Pharmacological and genetic inhibition of S1PR2 significantly suppressed their phosphorylation in response to H2O2. Especially lentivirus-mediated knockdown of S1PR2 inhibited H2O2-induced ZO-1 redistribution and paracellular hyperpermeability. Using the permanent middle cerebral artery occlusion (pMCAO) mouse model, we found JTE013 pretreatment markedly reduced Evans blue dye (EBD) extravasation and reversed the decrease in VE-cadherin, occludin, claudin-5 and CD31 expression in infarcted hemisphere. Lentivirus-mediated S1PR2 knockdown also attenuated EBD extravasation. Furthermore, JTE013 pretreatment attenuated neurological deficit, brain edema and infarction volume. Therefore, our findings suggest the protective effect of JTE013 on brain endothelial barrier integrity is likely mediated by suppressing p38 and Erk1/2-dependent cPLA(2) phosphorylation under oxidative stress.