ABCC1 缺乏通过损害耳蜗抗氧化能力增强了小鼠噪声诱导的听力损失。
ABCC1 deficiency potentiated noise-induced hearing loss in mice by impairing cochlear antioxidant capacity.
机构信息
Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China; National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Otolaryngology-Head and Neck Surgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China.
出版信息
Redox Biol. 2024 Aug;74:103218. doi: 10.1016/j.redox.2024.103218. Epub 2024 Jun 1.
The ABCC1 gene belongs to the ATP-binding cassette membrane transporter superfamily, which plays a crucial role in the efflux of various endogenous and exogenous substances. Mutations in ABCC1 can result in autosomal dominant hearing loss. However, the specific roles of ABCC1 in auditory function are not fully understood. Through immunofluorescence, we found that ABCC1 was expressed in microvascular endothelial cells (ECs) of the stria vascularis (StV) in the murine cochlea. Then, an Abcc1 knockout mouse model was established by using CRISPR/Cas9 technology to elucidate the role of ABCC1 in the inner ear. The ABR threshold did not significantly differ between WT and Abcc1 mice at any age studied. After noise exposure, the ABR thresholds of the WT and Abcc1 mice were significantly elevated. Interestingly, after 14 days of noise exposure, ABR thresholds largely returned to pre-exposure levels in WT mice but not in Abcc1 mice. Our subsequent experiments showed that microvascular integrity in the StV was compromised and that the number of outer hair cells and the number of ribbons were significantly decreased in the cochleae of Abcc1 mice post-exposure. Besides, the production of ROS and the accumulation of 4-HNE significantly increased. Furthermore, StV microvascular ECs were cultured to elucidate the role of ABCC1 in these cells under glucose oxidase challenge. Notably, 30 U/L glucose oxidase (GO) induced severe oxidative stress damage in Abcc1 cells. Compared with WT cells, the ROS and 4-HNE levels and the apoptotic rate were significantly elevated in Abcc1 cells. In addition, the reduced GSH/GSSG ratio was significantly decreased in Abcc1 cells after GO treatment. Taken together, Abcc1 mice are more susceptible to noise-induced hearing loss, possibly because ABCC1 knockdown compromises the GSH antioxidant system of StV ECs. The exogenous antioxidant N-acetylcysteine (NAC) may protect against oxidative damage in Abcc1 murine cochleae and ECs.
ABCC1 基因属于 ATP 结合盒膜转运体超家族，在各种内源性和外源性物质的外排中起着至关重要的作用。ABCC1 基因突变可导致常染色体显性遗传性听力损失。然而，ABCC1 在听觉功能中的具体作用尚不完全清楚。通过免疫荧光，我们发现 ABCC1 在小鼠耳蜗中的血管纹微血管内皮细胞（ECs）中表达。然后，我们使用 CRISPR/Cas9 技术建立了 Abcc1 基因敲除小鼠模型，以阐明 ABCC1 在内耳中的作用。在研究的任何年龄，ABCC1 敲除小鼠与野生型（WT）小鼠的 ABR 阈值均无显著差异。在噪声暴露后，WT 和 Abcc1 小鼠的 ABR 阈值均显著升高。有趣的是，在噪声暴露 14 天后，WT 小鼠的 ABR 阈值基本恢复到暴露前水平，但 Abcc1 小鼠则没有。我们随后的实验表明，ABCC1 敲除小鼠耳蜗中的血管纹微血管完整性受损，外毛细胞数量和连接蛋白数量明显减少。此外，ROS 的产生和 4-HNE 的积累显著增加。此外，还培养了血管纹微血管内皮细胞，以阐明 ABCC1 在葡萄糖氧化酶（GO）刺激下这些细胞中的作用。值得注意的是，30 U/L 的 GO 诱导 Abcc1 细胞发生严重的氧化应激损伤。与 WT 细胞相比，Abcc1 细胞中的 ROS 和 4-HNE 水平以及细胞凋亡率显著升高。此外，GO 处理后 Abcc1 细胞中的还原型谷胱甘肽（GSH）/氧化型谷胱甘肽（GSSG）比值显著降低。总之，ABCC1 敲除小鼠对噪声诱导的听力损失更为敏感，可能是因为 ABCC1 敲低会损害血管纹 ECs 的 GSH 抗氧化系统。外源性抗氧化剂 N-乙酰半胱氨酸（NAC）可能会保护 Abcc1 小鼠耳蜗和 ECs 免受氧化损伤。
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