DEL-1通过AMPK/自噬介导的内质网应激抑制减轻庆大霉素诱导的毛细胞铁死亡和凋亡

文献信息

中文摘要

假设： 发育内皮位点-1（DEL-1）是一种肌因子，已在多种实验模型中被证明可减轻内质网（ER）应激。本研究旨在探讨DEL-1对庆大霉素（GT）诱导的培养毛细胞样细胞耳毒性的影响。
背景： 长期使用GT治疗感染会诱导内耳ER应激，导致毛细胞样细胞死亡，并因此造成听力损失。
方法： 通过Western blot分析检测蛋白表达，并评估细胞活力、caspase 3活性和铁水平。通过TUNEL染色鉴定凋亡细胞。
结果： GT暴露在HEI-OC1细胞中触发铁死亡、凋亡和ER应激，而DEL-1处理可逆转上述所有变化。DEL-1还促进AMP活化蛋白激酶（AMPK）磷酸化和自噬。在GT存在的情况下，用siRNA或3-甲基腺嘌呤（3-MA）抑制AMPK会降低DEL-1的保护作用。
结论： 这些发现表明，DEL-1通过AMPK/自噬信号减轻ER应激，从而减少GT处理的毛细胞样细胞中的铁死亡和凋亡。这些发现表明，DEL-1作为一种肌肉分泌蛋白，可能为GT诱导的听力损失提供一种治疗策略。

英文摘要

HYPOTHESIS: Developmental endothelial locus-1 (DEL-1), a myokine, has been shown to reduce endoplasmic reticulum (ER) stress in various experimental models. This study aimed to examine the impact of DEL-1 on gentamicin (GT)-induced ototoxicity in cultured hair cell-like cells.
BACKGROUND: The long-term use of GTs for treating infections induces ER stress in the inner ear, leading to hair cell-like death and, as a result, hearing loss.
METHODS: Protein expression was measured via Western blot analysis, and cell viability, caspase 3 activity, and iron levels were assessed. Apoptotic cells were identified via TUNEL staining.
RESULTS: GT exposure triggered ferroptosis, apoptosis, and ER stress in HEI-OC1 cells, all of which were reversed by DEL-1 treatment. DEL-1 also promoted AMP-activated protein kinase (AMPK) phosphorylation and autophagy. Inhibition of AMPK with siRNA or 3-methyladenine (3-MA) reduced the protective effects of DEL-1 in the presence of GT.
CONCLUSION: These findings suggest that DEL-1 mitigates ER stress via AMPK/autophagy signaling, reducing ferroptosis and apoptosis in GT-treated hair cell-like cells. These findings indicate that DEL-1, a muscle-secreted protein, may offer a therapeutic strategy for GT-induced hearing loss.