SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-kappa B p65 acetylation and activation
SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-kappa B p65 acetylation and activation
复制标题
SIRT2 抑制通过增强 NF-kappa B p65 乙酰化和激活，加剧实验性脑外伤中的神经炎症和血脑屏障破坏
DOI：
10.1111/jnc.13423
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发表时间：
2016
影响因子：
4.7
通讯作者：
Ying WH
中科院分区：
文献类型：
--
作者：
Yuan Fang;Xu Zhi-Ming;Ding Jun;Tian Heng-Li;Lu Li-Yan;Nie Hui;Ying Wei-Hai;Tian HL;Ying WH
Sirtuin 2 （SIRT2）是NAD+依赖性蛋白去乙酰化酶Sirtuin家族的一员。近年来，SIRT2抑制已成为神经退行性疾病的一种有希望的治疗方法。然而，到目前为止，还没有证据表明SIRT2在创伤性脑损伤（TBI）中具有特定的作用。我们利用控制性皮质冲击（CCI）损伤模型研究了SIRT2抑制对实验性TBI的影响。成年雄性小鼠分别接受CCI或假手术。损伤前30分钟给予选择性脑渗透性SIRT2抑制剂AK - 7。与对照组相比，AK‐7 （20 mg/kg）处理小鼠脑损伤后脑水肿病变体积和脑含水量显著增加（分别在第1天和第3天p< 0.05）。同时，AK‐7在CCI后第3天和第7天显著加重了神经行为缺陷。此外，在SIRT2抑制后，血脑屏障破坏和基质金属蛋白酶(MMP) - 9活性增加。AK‐7处理增加了TBI诱导的体内和体外小胶质细胞的激活，伴随着炎症细胞因子的表达和释放的大量增加。从机制上说，SIRT2抑制增加了NF - κB p65的K310乙酰化和核易位，导致NF - κB活化增强，并上调其靶基因，包括水通道蛋白4 （AQP4）、MMP - 9和促炎细胞因子。总之，这些数据表明SIRT2抑制通过增加NF - κB p65乙酰化和激活而加重TBI。我们的发现为SIRT2的抗炎作用提供了额外的证据。SIRT2是NAD+依赖性蛋白去乙酰化酶sirtuin家族的一员。我们的研究表明，SIRT2抑制剂AK‐7通过NF‐κB p65乙酰化和核易位增加的潜在机制加重了创伤性脑损伤（TBI），导致NF‐κB靶基因上调，包括水通道蛋白4 （AQP4）、基质金属蛋白酶9 （MMP‐9）和促炎细胞因子。我们的发现为SIRT2的抗炎作用提供了额外的证据。
Sirtuin 2 (SIRT2) is a member of the sirtuin family of NAD+‐dependent protein deacetylases. In recent years, SIRT2 inhibition has emerged as a promising treatment for neurodegenerative diseases. However, to date, there is no evidence of a specific role for SIRT2 in traumatic brain injury (TBI). We investigated the effects of SIRT2 inhibition on experimental TBI using the controlled cortical impact (CCI) injury model. Adult male mice underwent CCI or sham surgery. A selective brain‐permeable SIRT2 inhibitor, AK‐7, was administrated 30 min before injury. The volume of the brain edema lesion and the water content of the brain were significantly increased in mice treated with AK‐7 (20 mg/kg), compared with the vehicle group, following TBI (p< 0.05 at 1 day andp< 0.05 at 3 days, respectively). Concomitantly, AK‐7 administration greatly worsened neurobehavioral deficits on days 3 and 7 after CCI. Furthermore, blood–brain barrier disruption and matrix metalloproteinases (MMP)‐9 activity increased following SIRT2 inhibition. AK‐7 treatment increased TBI‐induced microglial activation bothin vivoandin vitro, accompanied by a large increase in the expression and release of inflammatory cytokines. Mechanistically, SIRT2 inhibition increased both K310 acetylation and nuclear translocation of NF‐κB p65, leading to enhanced NF‐κB activation and up‐regulation of its target genes, including aquaporin 4 (AQP4), MMP‐9, and pro‐inflammatory cytokines. Together, these data demonstrate that SIRT2 inhibition exacerbates TBI by increasing NF‐κB p65 acetylation and activation. Our findings provide additional evidence of an anti‐inflammatory effect of SIRT2.SIRT2 is a member of the sirtuin family of NAD+‐dependent protein deacetylases. Our study suggests that the SIRT2 inhibitor AK‐7 exacerbates traumatic brain injury (TBI) via a potential mechanism involving increased acetylation and nuclear translocation of NF‐κB p65, resulting in up‐regulation of NF‐κB target genes, including aquaporin 4 (AQP4), matrix metalloproteinase 9 (MMP‐9), and pro‐inflammatory cytokines. Our findings provide additional evidence of an anti‐inflammatory effect of SIRT2.