HDAC4/5-HMGB1 signalling mediated by NADPH oxidase activity contributes to cerebral ischaemia/reperfusion injury.
HDAC4/5-HMGB1 signalling mediated by NADPH oxidase activity contributes to cerebral ischaemia/reperfusion injury.
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NADPH氧化酶活性介导的HDAC4/5-HMGB1信号传导导致脑缺血/再灌注损伤
DOI：
10.1111/jcmm.12040
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发表时间：
2013-04
影响因子：
5.3
通讯作者：
Yi F
中科院分区：
文献类型：
--
作者：
He M;Zhang B;Wei X;Wang Z;Fan B;Du P;Zhang Y;Jian W;Chen L;Wang L;Fang H;Li X;Wang PA;Yi F
组蛋白去乙酰化酶（HDACs）介导的表观遗传机制在组蛋白乙酰化和基因转录的内稳态中起着关键作用。HDAC抑制剂在包括阿尔茨海默病和缺血性脑卒中在内的多种神经系统疾病的动物模型中显示出神经保护特性。然而，一些研究也报道了HDAC酶在包括缺血应激在内的几种病理状况下发挥保护作用。这些复杂的结果表明了每种HDAC蛋白在不同疾病状态下的特定作用。然而，与缺血性脑卒中相关的HDAC亚型仍不清楚。因此，在本研究中，我们使用体内大脑中动脉闭塞（MCAO）模型以及体外氧糖剥夺模型培养细胞，以研究HDACs的表达模式，并探索单个HDACs在缺血性脑卒中中的作用。我们的结果表明，抑制NADPH氧化酶活性可改善脑缺血/再灌注（I/R）损伤，并且在依赖Zn2+的HDACs中，HDAC4和HDAC5在体内和体外均显著降低，而这种降低可被NADPH氧化酶抑制剂夹竹桃麻素逆转。我们进一步发现，在PC12细胞中，HDAC4和HDAC5通过抑制高迁移率族蛋白B1（HMGB1，一种急性损伤后组织损伤的核心介质）的表达和释放来提高细胞活力。我们的研究结果首次提供了证据，表明NADPH氧化酶介导的HDAC4和HDAC5表达通过HMGB1信号通路促进脑缺血损伤，这提示阐明大脑中单个HDACs的作用非常重要，并且需要开发特异性更强的HDAC抑制剂，以制定治疗脑卒中的有效治疗策略。
Histone deacetylases (HDACs)-mediated epigenetic mechanisms play critical roles in the homeostasis of histone acetylation and gene transcription. HDAC inhibitors have displayed neuroprotective properties in animal models for various neurological diseases including Alzheimer's disease and ischaemic stroke. However, some studies have also reported that HDAC enzymes exert protective effects in several pathological conditions including ischaemic stress. The mixed results indicate the specific roles of each HDAC protein in different diseased states. However, the subtypes of HDACs associated with ischaemic stroke keep unclear. Therefore, in this study, we used an in vivo middle cerebral artery occlusion (MCAO) model and in vitro cell cultures by the model of oxygen glucose deprivation to investigate the expression patterns of HDACs and explore the roles of individual HDACs in ischaemic stroke. Our results showed that inhibition of NADPH oxidase activity ameliorated cerebral ischaemia/reperfusion (I/R) injury and among Zn2+-dependent HDACs, HDAC4 and HDAC5 were significantly decreased both in vivo and in vitro, which can be reversed by NADPH oxidase inhibitor apocynin. We further found that both HDAC4 and HDAC5 increased cell viability through inhibition of HMGB1, a central mediator of tissue damage following acute injury, expression and release in PC12 cells. Our results for the first time provide evidence that NADPH oxidase-mediated HDAC4 and HDAC5 expression contributes to cerebral ischaemia injury via HMGB1 signalling pathway, suggesting that it is important to elucidate the role of individual HDACs within the brain, and the development of HDAC inhibitors with improved specificity is required to develop effective therapeutic strategies to treat stroke.
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DOI：
10.1124/jpet.108.149484
发表时间：
2009-06-01
影响因子：
3.5
作者：
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DOI：
10.1093/jnen/62.4.329
发表时间：
2003-04-01
影响因子：
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