Sirt1-Sirt3 axis regulates human blood-brain barrier permeability in response to ischemia.
Sirt1-Sirt3 axis regulates human blood-brain barrier permeability in response to ischemia.
复制标题
Sirt1-Sirt3 轴调节人血脑屏障通透性以应对缺血
DOI：
10.1016/j.redox.2017.09.016
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发表时间：
2018-04
期刊：
影响因子：
11.4
通讯作者：
Jiang XF
中科院分区：
文献类型：
--
作者：
Chen T;Dai SH;Li X;Luo P;Zhu J;Wang YH;Fei Z;Jiang XF
Sirtuin1 （Sirt1）和Sirtuin3 （Sirt3）是沉默信息调节因子2 （Sir2）蛋白家族中两个特性良好的成员。Sirt1和Sirt3都在抵抗细胞应激中发挥重要作用，但这两种sirtuins之间的相互作用尚未完全确定。在这项研究中，我们研究了Sirt1-Sirt3轴在体外缺血后血脑屏障（BBB）通透性中的作用。体外培养人脑微血管内皮细胞和星形胶质细胞，模拟血脑屏障，并进行氧糖剥夺（OGD）模拟缺血。经上皮电阻（TEER）结果显示，通过siRNA或saleramide抑制Sirt1可显著降低血脑屏障的通透性，而敲低Sirt3可增加血脑屏障的通透性。此外，Sirt1通过抑制AMPK-PGC1通路调节OGD后Sirt3的表达。AMPK抑制剂化合物C的应用部分阻止了Sirt1-Sirt3轴对OGD后血脑屏障通透性的影响。流式细胞术和细胞色素c释放结果表明Sirt1和Sirt3在ogd诱导的细胞凋亡中发挥相反的作用。此外，Sirt1的抑制被证明可以减弱线粒体活性氧（ROS）的产生，这有助于Sirt1- sirt3轴诱导的血脑屏障通透性和细胞损伤的调节。综上所述，这些发现表明Sirt1-Sirt3轴可能在血脑屏障生理学中发挥重要的调节作用，并可能通过调节线粒体ROS的产生成为缺血性卒中的治疗靶点。
Sirtuin1 (Sirt1) and Sirtuin3 (Sirt3) are two well-characterized members of the silent information regulator 2 (Sir2) family of proteins. Both Sirt1 and Sirt3 have been shown to play vital roles in resistance to cellular stress, but the interaction between these two sirtuins has not been fully determined. In this study, we investigated the role of Sirt1-Sirt3 axis in blood-brain barrier (BBB) permeability after ischemia in vitro. Human brain microvascular endothelial cells and astrocytes were co-cultured to model the BBB in vitro and oxygen and glucose deprivation (OGD) was performed to mimic ischemia. The results of transepithelial electrical resistance (TEER) showed that suppression of Sirt1 via siRNA or salermide significantly decreased BBB permeability, whereas Sirt3 knockdown increased BBB permeability. In addition, Sirt1 was shown to regulate Sirt3 expression after OGD through inhibiting the AMPK-PGC1 pathway. Application of the AMPK inhibitor compound C partially prevented the effects of Sirt1-Sirt3 axis on BBB permeability after OGD. The results of flow cytometry and cytochrome c release demonstrated that Sirt1 and Sirt3 exert opposite effects on OGD-induced apoptosis. Furthermore, suppression of Sirt1 was shown to attenuate mitochondrial reactive oxygen species (ROS) generation, which contribute to the Sirt1-Sirt3 axis-induced regulation of BBB permeability and cell damage. In summary, these findings demonstrate that the Sirt1-Sirt3 axis might act as an important modulator in BBB physiology, and could be a therapeutic target for ischemic stroke via regulating mitochondrial ROS generation.
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影响因子：
5.6
作者：
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影响因子：
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