Department of Molecular and Cellular Oncology, University Hospital of Mainz, Mainz, Germany.
Cell Death Dis. 2010 Jul 1;1(7):e51. doi: 10.1038/cddis.2010.25.
Hearing impairment caused by ototoxic insults, such as noise or gentamicin is a worldwide health problem. As the molecular circuitries involved are not yet resolved, current otoprotective therapies are rather empirical than rational. Here, immunohistochemistry and western blotting showed that the cytoprotective protein survivin is expressed in the human and guinea pig cochlea. In the guinea pig model, moderate noise exposure causing only a temporary hearing impairment transiently evoked survivin expression in the spiral ligament, nerve fibers and the organ of Corti. Mechanistically, survivin upregulation may involve nitric oxide (NO)-induced Akt signaling, as enhanced expression of the endothelial NO synthase and phosphorylated Akt were detectable in some surviving-positive cell types. In contrast, intratympanic gentamicin injection inducing cell damage and permanent hearing loss correlated with attenuated survivin levels in the cochlea. Subsequently, the protective activity of the human and the guinea pig survivin orthologs against the ototoxin gentamicin was demonstrated by ectopic overexpression and RNAi-mediated depletion studies in auditory cells in vitro. These data suggest that survivin represents an innate cytoprotective resistor against stress conditions in the auditory system. The pharmacogenetic modulation of survivin may thus provide the conceptual basis for the rational design of novel therapeutic otoprotective strategies.
耳毒性损伤引起的听力损失，如噪音或庆大霉素，是一个全球性的健康问题。由于涉及的分子电路尚未解决，目前的耳保护治疗方法更多是经验性的，而非基于理性的。在这里，免疫组织化学和 Western blot 显示，细胞保护蛋白 survivin 在人和豚鼠耳蜗中表达。在豚鼠模型中，适度的噪声暴露只会暂时引起听力障碍，短暂地诱导螺旋韧带、神经纤维和 Corti 器中的 survivin 表达。从机制上讲，survivin 的上调可能涉及一氧化氮（NO）诱导的 Akt 信号通路，因为一些存活阳性细胞类型中可检测到内皮型一氧化氮合酶和磷酸化 Akt 的增强表达。相比之下，鼓室内注射庆大霉素引起细胞损伤和永久性听力损失，与耳蜗中 survivin 水平降低相关。随后，通过体外在听觉细胞中进行的异位过表达和 RNAi 介导的耗竭研究，证明了人和豚鼠 survivin 同源物对耳毒性庆大霉素的保护活性。这些数据表明 survivin 是听觉系统应对应激条件的固有细胞保护抵抗者。因此，survivin 的药物遗传学调节可能为合理设计新型治疗性耳保护策略提供概念基础。
