The Role Of Histone Deacetylase4/5in The Development Of Cerebral Ischemia/Reperfusion Injury

Cerebrovascular diseases have been attracted a lot attentions globally because of its characteristics of high morbility, high rate of mutilation and high mortality. However its mechanisms are so sophisticated that we have not comprehended its mechanisms deeply and adopt the effective therapeutic measures. As for fundamental mechanism research, necrosis of neurons induced by oxidative stress more account for the cerebral ischemic damage. But how this process works together is still unkown. In the aspect of clinical care, the mainly therapeutic principle is make the reperfusion of the occlusive cerebral artery reality, change the situation of ischemic brain area short of blood and oxygen supply. The disadvantage of this therapy is that reperfusion step usually can not recover the cerebral function, and even aggravate the ischemic damage to some extent. So there is hardly any effective therapy for this ischemic stroke. This research is focus on how oxidative stress induce necrosis of neurons accounting for the cerebral ischemic damage from a brand new point and hypothesis.Epigenetic mechanisms is a new biology conception dating from80s20th century. This mechanisms is involved in lots of diseases. And it is also critical for the regulation of central nervous system. Among them, histone deacetylases (HDACs) play a key role in the homeostasis of histone acetylation and gene transcription. HDAC inhibitors have displayed neuroregenerative and neuroprotective properties in animal models for various neurological diseases including Alzheimer’s disease and stroke. By contrast, there is accumulating evidence that HDAC enzymes exert protective effects in several pathological conditions including ischemic stress. The mixed results indicate the specific roles of each HDAC protein and the possible function of distinct histone modification in different diseased states. However, up to date, the subtype of HDACs associated with ischemic stroke keeps unclear. Therefore, in the present study, we used an in vivo middle cerebral artery occlusion (MCAO) model and in vitro cell cultures by the model of oxygen glucose deprivation (OGD) to investigate the expression patterns of individual HDACs and explore the roles of individual HDACs in ischemic stroke. Our results showed that among Zn2+-dependent HDACs, HDAC4and HDAC5(class Ila HDACs) were significantly decreased both in vivo and in vitro, which can be reversed by NADPH oxidase inhibitor, apocynin. We further investigated the roles of HDAC4and HDAC5on the regulation of HMGB1, a central and necessary mediator of tissue damage following acute injury, showing that both HDAC4and HDAC5increased the viability of cells through inhibition of HMGB1expression and release. Our results for the first time provide evidence that NADPH oxidase-mediated HDAC4and HDAC5expression contributes to cerebral ischemia injury via HMGB1signaling pathway, suggesting that for the future research of HDAC therapeutics, 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 brain diseases.