Autophagy Attenuates Noise-Induced Hearing Loss by Reducing Oxidative Stress

作者：Yuan, Hu; Wang, Xianren; Hill, Kayla; Chen, Jun; Lemasters, John; Yang, Shi-Ming; Sha, Su-Hua^*

来源：Antioxidants and Redox Signaling, 2015, 22(15): 1308-1324.

DOI：10.1089/ars.2014.6004

• INNER-EAR
• HAIR-CELLS
• FREE-RADICALS
• COCHLEAR
• PATHWAY
• ACTIVATION
• INHIBITION
• INFLAMMATION
• SENSITIVITY
• MECHANISMS

Aims: Reactive oxygen species play a dual role in mediating both cell stress and defense pathways. Here, we used pharmacological manipulations and siRNA silencing to investigate the relationship between autophagy and oxidative stress under conditions of noise-induced temporary, permanent, and severe permanent auditory threshold shifts (temporary threshold shift [TTS], permanent threshold shift [PTS], and severe PTS [sPTS], respectively) in adult CBA/J mice. Results: Levels of oxidative stress markers (4-hydroxynonenal [4-HNE] and 3-nitrotyrosine [3-NT]) increased in outer hair cells (OHCs) in a noise-dose-dependent manner, whereas levels of the autophagy marker microtubule-associated protein light chain 3 B (LC3B) were sharply elevated after TTS but rose only slightly in response to PTS and were unaltered by sPTS noise. Furthermore, green fluorescent protein (GFP) intensity increased in GFP-LC3 mice after TTS-noise exposure. Treatment with rapamycin, an autophagy activator, significantly increased LC3B expression, while diminishing 4-HNE and 3-NT levels, reducing noise-induced hair cell loss, and, subsequently, noise-induced hearing loss (NIHL). In contrast, treatment with either the autophagy inhibitor 3-methyladenine (3MA) or LC3B siRNA reduced LC3B expression, increased 3-NT and 4-HNE levels, and exacerbated TTS to PTS. Innovation: This study demonstrates a relationship between oxidative stress and autophagy in OHCs and reveals that autophagy is an intrinsic cellular process that protects against NIHL by attenuating oxidative stress. Conclusions: The results suggest that the lower levels of oxidative stress incurred by TTS-noise exposure induce autophagy, which promotes OHC survival. However, excessive oxidative stress under sPTS-noise conditions overwhelms the beneficial potential of autophagy in OHCs and leads to OHC death and NIHL. Antioxid. Redox Signal. 22, 1308-1324.

• 出版日期2015-5-20
• 单位中国人民解放军总医院; 中国医科大学