Propofol improved hypoxia-impaired integrity of blood-brain barrier via modulating the expression and phosphorylation of zonula occludens-1
Propofol improved hypoxia-impaired integrity of blood-brain barrier via modulating the expression and phosphorylation of zonula occludens-1
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DOI：
10.1111/cns.13101
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发表时间：
2019-06-01
影响因子：
5.5
通讯作者：
Chen, Jia-Wei
中科院分区：
文献类型：
--
作者：
Chen, Wei;Ju, Xing-Zhu;Chen, Jia-Wei
目的缺氧可损伤血脑屏障（BBB）。异丙酚的神经保护作用已有报道。我们的目的是确定异丙酚是否以及如何改善缺氧诱导的血脑屏障完整性损伤。方法将小鼠脑微血管内皮细胞（MBMECs）与星形胶质细胞共培养，建立体外血脑屏障模型。观察缺氧和异丙酚对血脑屏障完整性的影响。进一步测定闭塞带-1 （ZO-1）的表达和磷酸化、缺氧诱导因子-1 α (HIF-1 α)和血管内皮生长因子（VEGF）的表达、细胞内钙浓度和Ca2+/钙调素依赖性蛋白激酶II （CAMKII）的活化。结果缺氧损伤血脑屏障完整性，异丙酚可保护血脑屏障完整性。缺氧降低ZO-1表达，诱导ZO-1磷酸化。这些影响被异丙酚减弱了。缺氧可使HIF-1 α和VEGF表达升高，异丙酚可减轻其表达。hif - α抑制剂和VEGF抑制剂逆转了缺氧介导的ZO-1抑制和血脑屏障完整性受损。此外，缺氧增加细胞内钙浓度，诱导CAMKII磷酸化，异丙酚可减轻这一作用。钙螯合剂和CAMKII抑制剂可改善缺氧诱导的ZO-1磷酸化和血脑屏障完整性受损。结论异丙酚对缺氧介导的血脑屏障完整性损伤具有保护作用。潜在的机制可能与ZO-1的表达和磷酸化有关。
Aims Hypoxia may damage blood-brain barrier (BBB). The neuroprotective effect of propofol has been reported. We aimed to identify whether and how propofol improved hypoxia-induced impairment of BBB integrity. Methods Mouse brain microvascular endothelial cells (MBMECs) and astrocytes were cocultured to establish in vitro BBB model. The effects of hypoxia and propofol on BBB integrity were examined. Further, zonula occludens-1 (ZO-1) expression and phosphorylation, hypoxia-inducible factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF) expression, intracellular calcium concentration and Ca2+/calmodulin-dependent protein kinase II (CAMKII) activation were measured. Results Hypoxia-impaired BBB integrity, which was protected by propofol. Hypoxia-reduced ZO-1 expression, while induced ZO-1 phosphorylation. These effects were attenuated by propofol. The expression of HIF-1 alpha and VEGF was increased by hypoxia and was alleviated by propofol. The hypoxia-mediated suppression of ZO-1 and impaired BBB integrity was reversed by HIF-alpha inhibitor and VEGF inhibitor. In addition, hypoxia increased the intracellular calcium concentration and induced the phosphorylation of CAMKII, which were mitigated by propofol. The hypoxia-induced phosphorylation of ZO-1 and impaired BBB integrity was ameliorated by calcium chelator and CAMKII inhibitor. Conclusion Propofol could protect against hypoxia-mediated impairment of BBB integrity. The underlying mechanisms may involve the expression and phosphorylation of ZO-1.