title: An otoprotective role for the apoptosis inhibitor protein survivin.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Oncology, University Hospital of Mainz, Mainz, Germany.
authors.forename: S K
authors.initials: SK
authors.lastname: Knauer
authors.forename: U-R
authors.initials: UR
authors.lastname: Heinrich
authors.forename: C
authors.initials: C
authors.lastname: Bier
authors.forename: N
authors.initials: N
authors.lastname: Habtemichael
authors.forename: D
authors.initials: D
authors.lastname: Docter
authors.forename: K
authors.initials: K
authors.lastname: Helling
authors.forename: W J
authors.initials: WJ
authors.lastname: Mann
authors.forename: R H
authors.initials: RH
authors.lastname: Stauber
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003051:Cochlea / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005839:Gentamicins / Q000633:toxicity; D006168:Guinea Pigs; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D000077022:Survivin; D015854:Up-Regulation
chemical_list: C107489:BIRC5 protein, human; D005839:Gentamicins; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt