HDAC2 Regulates Glial Cell Activation in Ischemic Mouse Retina.

Mi Sun Sung,Hwan Heo,So Young Kim,Helong Piao,Yue Guo,Sang Woo Park,Gwang Hyeon Eom

doi:10.3390/ijms20205159

Abstract

The current study was undertaken to investigate whether histone deacetylases (HDACs) can modulate the viability of retinal ganglion cells (RGCs) and the activity of glial cells in a mouse model of retinal ischemia-reperfusion (IR) injury. C57BL/6J mice were subjected to constant elevation of intraocular pressure for 60 min to induce retinal IR injury. Expression of macroglial and microglial cell markers (GFAP and Iba1), hypoxia inducing factor (HIF)-1α, and histone acetylation was analyzed after IR injury. To investigate the role of HDACs in the activation of glial cells, overexpression of HDAC1 and HDAC2 isoforms was performed. To determine the effect of HDAC inhibition on RGC survival, trichostatin-A (TSA, 2.5 mg/kg) was injected intraperitoneally. After IR injury, retinal GFAP, Iba1, and HIF-1α were upregulated. Conversely, retinal histone acetylation was downregulated. Notably, adenoviral-induced overexpression of HDAC2 enhanced glial activation following IR injury, whereas overexpression of HDAC1 did not significantly affect glial activation. TSA treatment significantly increased RGC survival after IR injury. Our results suggest that increased activity of HDAC2 is closely related to glial activation in a mouse model of retinal IR injury and inhibition of HDACs by TSA showed neuroprotective potential in retinas with IR injuries.

Highlights

The acetylation of histone N-terminal tails controls the interaction between histones and DNA in chromatin and results in chromatin remodeling, which is a key step in transcriptional regulation [1,2]
Western blot and immunohistochemical analysis showed that glial fibrillary acidic protein (GFAP) and Iba1 expression peaked at 3 days after IR injury relative to the control (2.08 ± 0.42-fold and 1.90 ± 0.31-fold, respectively; both p < 0.01, Figure 1A–D)
hypoxia inducing factor (HIF)-1α expression peaked at 3 days after retinal ischemia relative to the control (2.32 ± 0.10-fold; p < 0.01, Figure 1E,F), and its upregulation remained significant for all the following time points after IR injury

Summary

Introduction

The acetylation of histone N-terminal tails controls the interaction between histones and DNA in chromatin and results in chromatin remodeling, which is a key step in transcriptional regulation [1,2]. Hyperacetylation is associated with transcriptional activation, whereas deacetylation is associated with transcriptional repression. The equilibrium between the activity of histone acetyltransferases (HAT) and histone deacetylases (HDAC) is tightly regulated in neurons under normal conditions. The impairment of acetylation homeostasis results in a shift toward deacetylation, which is a frequent molecular feature of neurodegenerative diseases [3,4]. The inhibition of HDACs has been attempted to restore homeostatic conditions in such diseases. The application of valprioc acid, a class I and IIa HDAC inhibitor, or trichostatin A (TSA), a pan-HDAC inhibitor, was reported to be neuroprotective in retinal ganglion cells (RGC) in an animal model of optic nerve crushing, retinal ischemia, and chronic ocular hypertension [5,6,7,8]

Methods

Results

Conclusion