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Abstract
Histone deacetylase (HDAC) 9, a member of class II HDACs, regulates a wide variety of normal and abnormal physiological functions, which is usually expressed at high levels in the brain and skeletal muscle. Although studies have highlighted the importance of HDAC‐mediated epigenetic processes in the development of ischaemic stroke and very recent genome‐wide association studies have identified a variant in HDAC9 associated with large‐vessel ischemic stroke, the molecular events by which HDAC9 induces cerebral injury keep unclear. In this study, we found that HDAC9 was up‐regulated in the ischaemic cerebral hemisphere after cerebral ischaemia/reperfusion (I/R) injury in rats and in vivo gene silencing of HDAC9 by recombinated lentivirus infection in the brain reduced cerebral injury in experimental stroke. We further demonstrated that HDAC9 contributed to oxygen‐glucose deprivation‐induced brain microvessel endothelial cell dysfunction as demonstrated by the increased inflammatory responses, cellular apoptosis and endothelial cell permeability dysfunction accompanied by reduced expression of tight‐junction proteins. We further found that HDAC9 suppressed autophagy, which was associated with endothelial dysfunction. This study for the first time provides direct evidence that HDAC9 contributes to endothelial cell injury and demonstrates that HDAC9 is one of critical components of a signal transduction pathway that links cerebral injury to epigenetic modification in the brain.
Highlights
The pathogenesis of ischaemic cerebral injury is multifactorial and strategies aimed to reduce oxidative stress, inflammation and intracellular calcium release have been considered for the treatment of stroke [1], the pre-clinical protective agents targeting a specific pathway failed to demonstrate clinical efficacy
We found that HDAC9 was up-regulated in the ischaemic cerebral hemisphere after cerebral I/R injury in rats and in vivo gene silencing of HDAC9 by recombinated lentivirus infection and stereotaxic a 2016 The Authors
We further demonstrated that endothelial injury was associated with exacerbating inflammation and suppressing autophagy induced by HDAC9
Summary
The pathogenesis of ischaemic cerebral injury is multifactorial and strategies aimed to reduce oxidative stress, inflammation and intracellular calcium release have been considered for the treatment of stroke [1], the pre-clinical protective agents targeting a specific pathway failed to demonstrate clinical efficacy. Histone deacetylases (HDACs)-mediated epigenetic mechanisms play important roles in the homoeostasis of histone acetylation and gene transcription. HDAC1 gain-of-function transgene exhibits potent protection against DNA damage and neurotoxicity [6] rather than the deterioration of cerebral injury [7, 8]. It is necessary to elucidate the functional role of individual HDACs in ischaemic stroke. Our previous studies have characterized the expression patterns of individual HDACs in rats after cerebral ischaemia/reperfusion (I/R) injury. The role of HDAC9 in ischaemic stroke keeps unknown
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