Sirtuin 6 protects the brain from cerebral ischemia/reperfusion injury through NRF2 activation.
Sirtuin 6 protects the brain from cerebral ischemia/reperfusion injury through NRF2 activation.
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Sirtuin 6 通过 NRF2 激活保护大脑免受脑缺血/再灌注损伤。
DOI：
10.1016/j.neuroscience.2017.09.035
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发表时间：
2017
期刊：
影响因子：
3.3
通讯作者：
Qian Chuanyun
中科院分区：
文献类型：
--
作者：
Zhang Wei;Wei Rui;Zhang Lin;Tan Yang;Qian Chuanyun
Sirtuin 6（SIRT 6）是NAD（+）依赖性去乙酰化酶的Sirtuin家族的一员，已被证明在心肌缺血/再灌注（I/R）中产生有益作用。然而，SIRT 6在脑I/R中的作用很大程度上尚不清楚。在本研究中，我们研究了SIRT 6过表达在体内小鼠脑I/R模型和体外OGD/R刺激的neuro-2a神经母细胞瘤细胞中调节I/R损伤的作用。结果发现，脑I/R（1h/24 h）可导致大脑皮质SIRT 6表达降低（P< 0.01）。通过体内基因转移在脑中过表达SIRT 6增强了抗氧化剂NRF 2信号传导（P< 0.05），降低了氧化应激（P< 0.05），并减轻了脑I/R诱导的脑组织损伤和神经功能障碍（P< 0.05）。SIRT 6过表达的这些神经保护作用在NRF 2敲除小鼠中被消除。在neuro-2A神经母细胞瘤细胞中，SIRT 6过表达增加了总的和核的NRF 2水平（P<0.05），降低了氧化应激（P< 0.05），并减弱了OGD/R诱导的细胞死亡（P< 0.05）;这些保护作用被NRF 2敲低阻断（P< 0.05）。此外，在OGD/R刺激的neuro-2A细胞中，SIRT 6过表达产生了与抗氧化剂NAC诱导的保护作用相似的保护作用，但当SIRT 6过表达与NAC联合使用时，没有检测到额外的益处（P> 0.05）。这些发现提供了SIRT 6可以通过NRF 2激活抑制氧化应激来保护大脑免受脑I/R损伤的证据。因此，SIRT 6可能作为缺血性卒中的潜在治疗靶点。
Sirtuin 6 (SIRT6), a member of the sirtuin family of NAD(+)-dependent deacetylases, has been shown to produce beneficial effects in myocardial ischemia/reperfusion (I/R). However, the role of SIRT6 in cerebral I/R is largely unclear. In this study, we investigated the effects of SIRT6 overexpression in regulating I/R injury in a mouse cerebral I/R modelin vivoand in oxygen-glucose-deprivation/reoxygenation (OGD/R)-stimulated neuro-2a neuroblastoma cellsin vitro. We found that cerebral I/R (1 h/24 h) resulted in decreased SIRT6 expression in the cerebral cortex (P< 0.01). SIRT6 overexpression in the brain byin vivogene transfer enhanced the antioxidant NRF2 signaling (P< 0.05), reduced oxidative stress (P< 0.05), and attenuated cerebral I/R-induced brain tissue damage and neurological deficits (P< 0.05). These neuroprotective effects of SIRT6 overexpression were abolished in NRF2 knockout mice. In neuro-2A neuroblastoma cells, SIRT6 overexpression increased total and nuclear NRF2 levels (P< 0.05), reduced oxidative stress (P< 0.05), and attenuated OGD/R-induced cell death (P< 0.05); these protective effects were blocked by NRF2 knockdown (P< 0.05). Moreover, in OGD/R-stimulated neuro-2A cells, SIRT6 overexpression produced similar protective effects to those induced by the antioxidant NAC, but no added benefits were detected when SIRT6 overexpression was used in combination with NAC (P> 0.05). These findings provide evidence that SIRT6 can protect the brain from cerebral I/R injury by suppressing oxidative stress via NRF2 activation. Thus, SIRT6 may serve as a potential therapeutic target for ischemic stroke.