Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death |
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Authors: | Mona Taleb Carlene S Brandon Fu-Shing Lee Kelly C Harris Wolfgang H Dillmann Lisa L Cunningham |
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Institution: | (1) Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Avenue, MSC 908, Charleston, SC 29425, USA;(2) Department of Otolaryngology–Head and Neck Surgery, Medical University of South Carolina, Charleston, SC 29425, USA;(3) Department of Endocrinology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA |
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Abstract: | Sensory hair cells of the inner ear are sensitive to death from aging, noise trauma, and ototoxic drugs. Ototoxic drugs include
the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to aminoglycosides results in hair cell death
that is mediated by specific apoptotic proteins, including c-Jun N-terminal kinase (JNK) and caspases. Induction of heat shock
proteins (Hsps) can inhibit JNK- and caspase-dependent apoptosis in a variety of systems. We have previously shown that heat
shock results in robust upregulation of Hsps in the hair cells of the adult mouse utricle in vitro. In addition, heat shock
results in significant inhibition of both cisplatin- and aminoglycoside-induced hair cell death. In this system, Hsp70 is
the most strongly induced Hsp, which is upregulated over 250-fold at the level of mRNA 2 h after heat shock. Hsp70 overexpression
inhibits aminoglycoside-induced hair cell death in vitro. In this study, we utilized Hsp70-overexpressing mice to determine
whether Hsp70 is protective in vivo. Both Hsp70-overexpressing mice and their wild-type littermates were treated with systemic
kanamycin (700 mg/kg body weight) twice daily for 14 days. While kanamycin treatment resulted in significant hearing loss
and hair cell death in wild-type mice, Hsp70-overexpressing mice were significantly protected against aminoglycoside-induced
hearing loss and hair cell death. These data indicate that Hsp70 is protective against aminoglycoside-induced ototoxicity
in vivo. |
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Keywords: | Cochlea Hearing loss Ototoxicity Aminoglycoside Kanamycin Hair cell |
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