Tumor necrosis factor receptor-associated factor 6 participates in early brain injury after subarachnoid hemorrhage in rats through inhibiting autophagy and promoting oxidative stress
Tumor necrosis factor receptor-associated factor 6 participates in early brain injury after subarachnoid hemorrhage in rats through inhibiting autophagy and promoting oxidative stress
复制标题
肿瘤坏死因子受体相关因子6通过抑制自噬、促进氧化应激参与大鼠蛛网膜下腔出血后早期脑损伤
DOI：
10.1111/jnc.14075
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发表时间：
2017-08-01
影响因子：
4.7
通讯作者：
Chen，Gang
中科院分区：
文献类型：
--
作者：
Dou，Yang;Shen，Haitao;Chen，Gang
肿瘤坏死因子受体相关因子6（TRAF 6）是TRAF家族的成员，是肿瘤坏死因子超家族和toll/IL-1受体（TIR）超家族的重要多功能细胞内适应素。TRAF 6已在几种中枢神经系统疾病中进行了研究，包括缺血性中风，创伤性脑损伤和神经退行性疾病，但其在蛛网膜下腔出血（SAH）中的作用尚未得到充分说明。本研究采用Sprague-Dawley大鼠蛛网膜下腔出血（SAH）模型，将0.3 mL非肝素化自体动脉血注入视交叉前池，探讨TRAF 6在SAH后早期脑损伤（EBI）中的表达水平变化及其潜在作用和机制。首先，与假手术组相比，SAH后TRAF 6的表达水平逐渐升高，并在24 h达到高峰。第二，研究结果表明，应用TRAF 6过表达质粒和基因沉默siRNA可以分别增加或减少TRAF 6的表达，并严重加重或减轻SAH后的EBI，包括神经元死亡、脑水肿和血脑屏障损伤。同时，自噬和氧化应激水平分别降低和升高。最后，利用缺乏E3泛素连接酶活性的TRAF 6突变体GFP-TRAF 6-C70 A来探讨TRAF 6在SAH中的作用机制，结果显示EBI和氧化应激降低，但自噬水平增加。总的来说，这些结果表明TRAF 6通过抑制自噬和促进氧化应激影响SAH后EBI的程度。
Tumor necrosis factor receptor‐associated factor 6 (TRAF6) is a member of the TRAF family and an important multifunctional intracellular adaptin of the tumor necrosis factor superfamily and toll/IL‐1 receptor (TIR) superfamily. TRAF6 has been studied in several central nervous system diseases, including ischemic stroke, traumatic brain injury, and neurodegenerative diseases, but its role in subarachnoid hemorrhage (SAH) has not been fully illustrated. This study was designed to explore changes of expression level and potential roles and mechanisms of TRAF6 in early brain injury (EBI) after SAH using a Sprague–Dawley rat model of SAH induced in 0.3 mL non‐heparinized autologous arterial blood injected into the pre‐chiasmatic cistern. First, compared with the sham group, we found that the expression levels of TRAF6 increased gradually and peaked at 24 h after SAH. Second, the results showed that application of TRAF6 over‐expression plasmid and genetic silencing siRNA could increase or decrease expression of TRAF6, respectively, and severely exacerbate or relieve EBI after SAH, including neuronal death, brain edema, and blood–brain barrier injury. Meanwhile, the levels of autophagy and oxidative stress were reduced and increased separately. Finally, GFP‐TRAF6‐C70A, which is a TRAF6 mutant that lacks E3 ubiquitin ligase activity, was used to explore the mechanism of TRAF6 in SAH, and the results showed that EBI and oxidative stress were reduced, but the levels of autophagy were increased under this condition. Collectively, these results indicated that TRAF6 affected the degree of EBI after SAH by inhibiting autophagy and promoting oxidative stress.