HDAC1 deregulation promotes neuronal loss and deficit of motor function in stroke pathogenesis

Jui-Sheng Chen,Yu-Ting Su,Chien-Yu Hsu,Aij-Lie Kwan,Patrick Ching-Ho Hsieh,Cheng-Loong Liang,Hao-Kuang Wang,Cheng-Chun Wu,Jia-Shing Chen

doi:10.1038/s41598-021-95837-3

Abstract

Stroke is a common cause of death worldwide and leads to disability and cognitive dysfunction. Ischemic stroke and hemorrhagic stroke are major categories of stroke, accounting for 68% and 32% of strokes, respectively. Each year, 15 million people experience stroke worldwide, and the stroke incidence is rising. Epigenetic modifications regulate gene transcription and play a major role in stroke. Accordingly, histone deacetylase 1 (HDAC1) participates in DNA damage repair and cell survival. However, the mechanisms underlying the role of HDAC1 in stroke pathogenesis are still controversial. Therefore, we investigated the role of HDAC1 in stroke by using a rat model of endothelin-1-induced brain ischemia. Our results revealed that HDAC1 was deregulated following stroke, and its expressional level and enzymatic activity were decreased. We also used MS-275 to inhibit HDAC1 function in rats exposed to ischemic insult. We found that HDAC1 inhibition promoted the infarct volume, neuronal loss, DNA damage, neuronal apoptosis after stroke, and levels of reactive oxygen species and inflammation cytokines. Additionally, HDAC1 inhibition deteriorated the behavioral outcomes of rats with ischemic insult. Overall, our findings demonstrate that HDAC1 participates in ischemic pathogenesis in the brain and possesses potential for use as a therapeutic target.

Highlights

Stroke is a common cause of death worldwide and leads to disability and cognitive dysfunction
The results indicated that compared with the sham brain, the ischemic brain exhibited lower levels of histone deacetylase 1 (HDAC1) (Fig. 1B), suggesting that HDAC1 is involved in ischemic pathogenesis
The result indicated that HDAC1 activity was repressed by ischemic insult (Fig. 1C); reduced HDAC1 activity was identified in the rat brain at 24 and 72 h after stroke

Summary

Introduction

Stroke is a common cause of death worldwide and leads to disability and cognitive dysfunction. Histone deacetylase 1 (HDAC1) participates in DNA damage repair and cell survival. We investigated the role of HDAC1 in stroke by using a rat model of endothelin-1-induced brain ischemia. Histone acetylation levels are determined by the equilibrium established between histone acetyltransferases and histone deacetylases (HDACs) that regulate transcription and other functions in the brain through chromatin conformation modulation. Pan-HDAC inhibitors significantly decrease neuronal injury and improve functional outcome in multiple preclinical models of focal ischemia[9,10]. Research reported that the levels of DNA transcription and protein translation of neuronal HDAC1 are downregulated following s troke[11]. Gain of HDAC1 function was demonstrated to have the potential to promote DNA damage repair and attenuate neuronal d egeneration[6]. Because pan-HDAC inhibitor (pan-HDAC1i) toxicity affects diverse central nervous system cell types and pan-HDACi exhibits unexpected inhibitory effects in unique cell types[13,14], identification of essential HDAC isoforms involved in stroke pathogenesis is required for developing therapeutic approaches for stroke

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