Open AccessHDAC 4/5‐ HMGB 1 signalling mediated by NADPH oxidase activity contributes to cerebral ischaemia/reperfusion injury
Author(s) -
He Min,
Zhang Bin,
Wei Xinbing,
Wang Ziying,
Fan Baoxia,
Du Pengchao,
Zhang Yan,
Jian Wencheng,
Chen Lin,
Wang Linlin,
Fang Hao,
Li Xiang,
Wang PingAn,
Yi Fan
Publication year - 2013
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12040
Subject(s) - nadph oxidase , neuroprotection , ischemia , pharmacology , apocynin , histone , histone deacetylase , microbiology and biotechnology , viability assay , chemistry , reactive oxygen species , medicine , biology , in vitro , biochemistry , gene
Histone deacetylases ( HDAC s)‐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 HDAC s 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 HDAC s and explore the roles of individual HDAC s in ischaemic stroke. Our results showed that inhibition of NADPH oxidase activity ameliorated cerebral ischaemia/reperfusion (I/R) injury and among Zn 2+ ‐dependent HDAC s, HDAC 4 and HDAC 5 were significantly decreased both in vivo and in vitro , which can be reversed by NADPH oxidase inhibitor apocynin. We further found that both HDAC 4 and HDAC 5 increased cell viability through inhibition of HMGB 1, a central mediator of tissue damage following acute injury, expression and release in PC 12 cells. Our results for the first time provide evidence that NADPH oxidase‐mediated HDAC 4 and HDAC 5 expression contributes to cerebral ischaemia injury via HMGB 1 signalling pathway, suggesting that it is important to elucidate the role of individual HDAC s within the brain, and the development of HDAC inhibitors with improved specificity is required to develop effective therapeutic strategies to treat stroke.