SIRT1 attenuates blood-spinal cord barrier disruption after spinal cord injury by deacetylating p66Shc.
SIRT1 attenuates blood-spinal cord barrier disruption after spinal cord injury by deacetylating p66Shc.
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DOI：
10.1016/j.redox.2023.102615
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发表时间：
2023-04
期刊：
影响因子：
11.4
通讯作者：
Yin, Guoyong
中科院分区：
文献类型：
--
作者：
Jiang, Tao;Qin, Tao;Gao, Peng;Tao, Zhiwen;Wang, Xiaowei;Wu, Mengyuan;Gu, Jun;Chu, Bo;Zheng, Ziyang;Yi, Jiang;Xu, Tao;Huang, Yifan;Liu, Hao;Zhao, Shujie;Ren, Yongxin;Chen, Jian;Yin, Guoyong
血脊髓屏障（BSCB）的破坏导致炎症细胞浸润和神经细胞死亡，从而导致脊髓损伤（SCI）后功能恢复不良。先前的研究表明Sirtuin 1 （SIRT1）是一种依赖NAD+的III类组蛋白去乙酰化酶，在内皮细胞中大量表达并促进内皮稳态。然而，SIRT1在脊髓损伤后BSCB功能中的作用仍不明确。在这里，我们报道SIRT1在脊髓内皮细胞中高表达，在脊髓损伤后其表达显著降低。通过内皮细胞特异性SIRT1敲除小鼠，我们观察到内皮细胞特异性SIRT1敲除加重了BSCB破坏，从而导致脊髓损伤后广泛的炎症、神经细胞死亡和功能恢复不良。相比之下，激动剂SRT1720激活SIRT1具有有益的作用。在体外，SIRT1的下调加重了il -1β诱导的内皮屏障破坏。而SIRT1过表达则具有保护作用。通过RNA-seq和IP/MS分析，我们确定了氧化还原蛋白p66Shc是SIRT1的潜在靶点。进一步的研究表明，SIRT1与p66Shc相互作用并使p66Shc去乙酰化，从而减轻氧化应激，保护内皮屏障功能。总的来说，我们的研究结果表明，SIRT1减少内皮细胞ROS的产生，并通过去乙酰化p66Shc来减轻脊髓损伤后BSCB的破坏，这表明SIRT1的激活有可能作为一种治疗方法来促进脊髓损伤后BSCB破坏的功能恢复。
Disruption of the blood-spinal cord barrier (BSCB) leads to inflammatory cell infiltration and neural cell death, thus, contributing to poor functional recovery after spinal cord injury (SCI). Previous studies have suggested that Sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, is abundantly expressed in endothelial cells and promotes endothelial homeostasis. However, the role of SIRT1 in BSCB function after SCI remains poorly defined. Here, we report that SIRT1 is highly expressed in spinal cord endothelial cells, and its expression significantly decreases after SCI. Using endothelial cell-specific SIRT1 knockout mice, we observed that endothelial cell-specific knockout of SIRT1 aggravated BSCB disruption, thus, resulting in widespread inflammation, neural cell death and poor functional recovery after SCI. In contrast, activation of SIRT1 by the agonist SRT1720 had beneficial effects. In vitro, knockdown of SIRT1 exacerbated IL-1β-induced endothelial barrier disruption in bEnd.3 cells, whereas overexpression of SIRT1 was protective. Using RNA-seq and IP/MS analysis, we identified p66Shc, a redox protein, as the potential target of SIRT1. Further studies demonstrated that SIRT1 interacts with and deacetylates p66Shc, thereby attenuating oxidative stress and protecting endothelial barrier function. Overall, our results indicate that SIRT1 decreases endothelial ROS production and attenuates BSCB disruption by deacetylating p66Shc after SCI, and suggest that SIRT1 activation has potential as a therapeutic approach to promote functional recovery against BSCB disruption following SCI.
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影响因子：
64.8
作者：
Guarani V;Deflorian G;Franco CA;Krüger M;Phng LK;Bentley K;Toussaint L;Dequiedt F;Mostoslavsky R;Schmidt MHH;Zimmermann B;Brandes RP;Mione M;Westphal CH;Braun T;Zeiher AM;Gerhardt H;Dimmeler S;Potente M
通讯作者：
Potente M
影响因子：
11.4
作者：
Ge X;Tang P;Rong Y;Jiang D;Lu X;Ji C;Wang J;Huang C;Duan A;Liu Y;Chen X;Chen X;Xu Z;Wang F;Wang Z;Li X;Zhao W;Fan J;Liu W;Yin G;Cai W
通讯作者：
Cai W
影响因子：
64.5
作者：
Giorgio, M;Migliaccio, E;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
9.3
作者：
Kong, Fan-Qi;Zhao, Shu-Jie;Fan, Jin
通讯作者：
Fan, Jin
DOI：
10.1006/bbrc.2000.3000
发表时间：
2000-07-05
影响因子：
3.1
作者：
Frye, RA
通讯作者：
Frye, RA