The 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 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 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 mice at any age studied. After noise exposure, the ABR thresholds of the WT and 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 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 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 cells. Compared with WT cells, the ROS and 4-HNE levels and the apoptotic rate were significantly elevated in cells. In addition, the reduced GSH/GSSG ratio was significantly decreased in cells after GO treatment. Taken together, mice are more susceptible to noise-induced hearing loss, possibly because ABCC1 knockdown compromises the GSH antioxidant system of StV ECs. The exogenous antioxidant -acetylcysteine (NAC) may protect against oxidative damage in murine cochleae and ECs.

中文翻译：

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ABCC1 缺陷通过损害耳蜗抗氧化能力而加剧噪音引起的小鼠听力损失


该基因属于ATP结合盒膜转运蛋白超家族，在各种内源性和外源性物质的流出中起着至关重要的作用。突变可导致常染色体显性听力损失。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在小鼠耳蜗血管纹（StV）的微血管内皮细胞（EC）中表达。然后，利用CRISPR/Cas9技术建立了基因敲除小鼠模型，以阐明ABCC1在内耳中的作用。在所研究的任何年龄，WT 小鼠和小鼠之间的 ABR 阈值没有显着差异。噪声暴露后，WT 和小鼠的 ABR 阈值显着升高。有趣的是，在噪声暴露 14 天后，WT 小鼠的 ABR 阈值大部分恢复到暴露前的水平，但小鼠则不然。我们随后的实验表明，暴露后，StV 中的微血管完整性受到损害，并且小鼠耳蜗中的外毛细胞数量和丝带数量显着减少。此外，ROS的产生和4-HNE的积累显着增加。此外，还培养了 StV 微血管 EC，以阐明 ABCC1 在葡萄糖氧化酶攻击下这些细胞中的作用。值得注意的是，30 U/L 葡萄糖氧化酶 (GO) 会诱导细胞严重氧化应激损伤。与WT细胞相比，细胞中ROS和4-HNE水平以及细胞凋亡率显着升高。此外，GO处理后细胞中GSH/GSSG比值显着降低。总而言之，小鼠更容易受到噪音引起的听力损失，可能是因为 ABCC1 敲低损害了 StV EC 的 GSH 抗氧化系统。 外源性抗氧化剂乙酰半胱氨酸（NAC）可以保护小鼠耳蜗和内皮细胞免受氧化损伤。