Heat Shock Factor 1 Prevents Age-Related Hearing Loss by Decreasing Endoplasmic Reticulum Stress.

Yun Yeong Lee,Jeong Hun Jang,In Hye Jeong,Hantai Kim,Eun Sol Gil,Yun-Hoon Choung

doi:10.3390/cells10092454

Abstract

Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the present study was to identify the role of HSF1 in ARHL. In this study, we demonstrated that the loss of inner and outer hair cells and their supporting cells was predominant in the high-frequency region (basal turn, 32 kHz) in ARHL cochleae. In the aging cochlea, levels of the ER stress marker proteins p-eIF2α and CHOP increased as HSF1 protein levels decreased. The levels of various heat shock proteins (HSPs) also decreased, including HSP70 and HSP40, which were markedly downregulated, and the expression levels of Bax and cleaved caspase-3 apoptosis-related proteins were increased. However, HSF1 overexpression showed significant hearing protection effects in the high-frequency region (basal turn, 32 kHz) by decreasing CHOP and cleaved caspase-3 and increasing the HSP40 and HSP70 proteins. These findings were confirmed by HSF1 functional studies using an auditory cell model. Therefore, we propose that HSF1 can function as a mediator to prevent ARHL by decreasing ER stress-dependent apoptosis in the aging cochlea.

Highlights

Age-related hearing loss (ARHL), a progressive form of bilateral hearing loss, is among the most common disorders affecting older people
In inner hair cells (IHCs), outer hair cell (OHC), and SPs of the OC, the expression of the endoplasmic reticulum (ER) stress markers p-eIF2α and C/EBP homologous protein (CHOP), as well as the apoptosis markers Bax and cleaved-caspase 3, were significantly higher in the aging group compared to the control group, indicating high ER stress and apoptosis (Figure 1D)
Of 20cell death, these results suggest that ER stress is involved in apoptosis during auditory12hair and that Heat shock factor 1 (HSF1) plays an important role in regulating this mechanism

Summary

Introduction

Age-related hearing loss (ARHL), a progressive form of bilateral hearing loss, is among the most common disorders affecting older people. Ototoxic drugs, or genetic factors can influence the onset of ARHL [1]. Previous studies have reported that mitochondrial DNA mutation during aging can lead to mitochondrial defects and generate reactive oxygen species (ROS), followed by an increase in apoptosis contributing to cochlear pathology [2,3]. The mechanisms underlying these processes remain unclear because insufficient studies have examined the various stress responses causing apoptosis in ARHL. The heat shock response or endoplasmic reticulum (ER) stress leads to activation of the genes encoding heat shock proteins (HSPs). HSPs function as molecular chaperones for the refolding or degradation of damaged proteins, thereby contributing to intracellular homeostasis

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