Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death

Taleb, Mona; Brandon, Carlene; Lee, Fu‐Shing; Harris, Kelly C.; Dillmann, Wolfgang H.; Cunningham, Lisa L.

doi:10.1007/s12192-008-0097-2

Cited by 51 publications

(47 citation statements)

References 57 publications

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“…These data are in agreement with our previously reported findings regarding the role of HSP70 as a mediator of the protective effect of heat shock against aminoglycosideinduced hair cell death (Taleb et al 2008;May et al 2013). However, constitutive expression of HSP70 conferred robust protection against aminoglycosideinduced hair cell death (Taleb et al 2008(Taleb et al , 2009) and only modest protection against cisplatin-induced hair cell death (Fig. 1D).…”

Section: Discussionmentioning

confidence: 98%

“…In order to determine if HSP70 is sufficient to protect hair cells against cisplatin-induced death, we utilized utricles from mice that constitutively express ratinducible HSP70 (rHSP70i CE) (Marber et al 1995;Kim et al 2006b;Taleb et al 2008Taleb et al , 2009). We first examined HSP induction in response to heat shock in utricles from rHSP70i CE mice and their wild-type littermates (Fig.…”

Section: Hsp Levels In Utricles From Rhsp70i Ce Mice and Their Wild-tmentioning

confidence: 99%

“…HSP70 inhibits multiple pro-apoptotic signals, including oligomerization of Bax, release of both cytochrome c and second mitochondria-derived activator of caspases (Smac) from mitochondria, formation of a functional apoptosome, and even cell death subsequent to caspase 3 activation (Jaattela et al 1998;Beere et al 2000;Tsuchiya et al 2003;Stankiewicz et al 2005;Jiang et al 2009;Evans et al 2010). Moreover, HSP70 inhibits aminoglycosideinduced hair cell death in vitro and hearing loss in vivo (Taleb et al 2008(Taleb et al , 2009May et al 2013). Our previous data indicate that HSP70 is the most highly induced HSP in response to heat shock in whole-organ cultures of utricles from mature mice (Cunningham and Brandon 2006;Taleb et al 2008;Francis et al 2011;May et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Baker

Roy

Brandon

et al. 2014

JARO

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Cisplatin is a highly successful and widely used chemotherapy for the treatment of various solid malignancies in both adult and pediatric patients. Side effects of cisplatin treatment include nephrotoxicity and ototoxicity. Cisplatin ototoxicity results from damage to and death of cells in the inner ear, including sensory hair cells. We showed previously that heat shock inhibits cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. Since heat shock protein 70 (HSP70) is the most upregulated HSP in response to heat shock, we investigated the role of HSP70 as a potential protectant against cisplatin-induced hair cell death. Our data using utricles from HSP70 −/− mice indicate that HSP70 is necessary for the protective effect of heat shock against cisplatin-induced hair cell death. In addition, constitutive expression of inducible HSP70 offered modest protection against cisplatin-induced hair cell death. We also examined a second heat-inducible protein, heme oxygenase-1 (HO-1, also called HSP32). HO-1 is an enzyme responsible for the catabolism of free heme. We previously showed that induction of HO-1 using cobalt protoporphyrin IX (CoPPIX) inhibits aminoglycoside-induced hair cell death. Here, we show that HO-1 also offers significant protection against cisplatin-induced hair cell death. HO-1 induction occurred primarily in resident macrophages, with no detectable expression in hair cells or supporting cells. Depletion of macrophages from utricles abolished the protective effect of HO-1 induction. Together, our data indicate that HSP induction protects against cisplatin-induced hair cell death, and they suggest that resident macrophages mediate the protective effect of HO-1 induction.

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Section: Discussionmentioning

confidence: 98%

Section: Hsp Levels In Utricles From Rhsp70i Ce Mice and Their Wild-tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Baker

Roy

Brandon

et al. 2014

JARO

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“…For example, PFTα can inhibit zebrafish p73 in vivo and mammalian cyclin D1 in vitro, while PFTμ inhibits hsp70 and can interfere with autophagy (Davidson et al 2008;Leu et al 2009;Sohn et al 2009;Pimkina and Murphy 2011). Hsp70 activation inhibits aminoglycoside-induced hair cell loss in mammalian models, making it unlikely that inhibiting hsp70 would exert a protective effect in zebrafish hair cells (Taleb et al 2008(Taleb et al , 2009). However, blocking autophagy does provide a modest protective effect from aminoglycoside damage in zebrafish (Coffin et al 2013), so we cannot rule out this off-target effect of PFTμ in our present study, nor can we be certain that PFTα or PFTμ are not exerting an influence on additional targets.…”

Section: P53 and Aminoglycoside Ototoxicitymentioning

confidence: 99%

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Coffin

Rubel

Raible

2013

JARO

100

116

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Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.

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“…The stressors examined include hyperthermia (the classic heat shock response) (Neely et al 1991;Dechesne et al 1992), whole body heat shock (Yoshida et al 1999), local hyperthermia (Sugahara et al 2003), transient ischemia (Myers et al 1992), cisplatin ototoxicity (Oh et al 2000), and noise overstimulation (Lim et al 1993;Yoshida et al 1999;Yoshida and Liberman 2000). Heat shock or overexpression of HSP70 also protects utricular cultures from death of hair cells due to aminoglycoside antibiotics or cisplatin (Taleb et al 2008(Taleb et al , 2009.…”

Section: Introductionmentioning

confidence: 99%

Induction of Heat Shock Proteins by Hyperthermia and Noise Overstimulation in Hsf1 −/− Mice

Gong

Fairfield

Fullarton

et al. 2011

JARO

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Diverse cellular and environmental stresses can activate the heat shock response, an evolutionarily conserved mechanism to protect proteins from denaturation. Stressors activate heat shock transcription factor 1 (HSF1), which binds to heat shock elements in the genes for heat shock proteins, leading to rapid induction of these important molecular chaperones. Both heat and noise stress are known to activate the heat shock response in the cochlea and protect it from subsequent noise trauma. However, the contribution of HSF1 to induction of heat shock proteins following noise trauma has not been investigated at the molecular level. We evaluated the role of HSF1 in the cochlea following noise stress by examining induction of heat shock proteins in Hsf1 +/− control and Hsf1 −/− mice. Heat stress rapidly induced expression of Hsp25, Hsp47, Hsp70.1, Hsp70.3, Hsp84, Hsp86, and Hsp110 in the cochleae of wild-type and Hsf1 +/− mice, but not in Hsf1 −/− mice, confirming the essential role of HSF1 in mediating the heat shock response. Exposure to broadband noise (2-20 kHz) at 106 dB SPL for 2 h produced partial hearing loss. Maximal induction of heat shock proteins occurred 4 h after the noise. In comparison to heat stress, noise stress resulted in lower induced levels of Hsp25, Hsp70.1, Hsp70.3, Hsp86, and Hsp110 in Hsf1 +/− mice. Induction of these heat shock proteins was attenuated, but not completely eliminated, in Hsf1 −/− mice. These same noise exposure conditions induced genes for several immediate early transcription factors and maximum induction occurred earlier than for heat shock proteins. Thus, additional signaling pathways and transcriptional regulators that are activated by noise probably contribute to induction of heat shock proteins in the cochlea.

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Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death

Cited by 51 publications

References 57 publications

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Induction of Heat Shock Proteins by Hyperthermia and Noise Overstimulation in Hsf1 −/− Mice

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