Overexpression of X-linked inhibitor of apoptosis protein protects against noise-induced hearing loss in mice

Abstract

Apoptosis is responsible for cochlear cell death induced by noise. Here, we show that transgenic (TG) mice that overexpress X-linked inhibitor of apoptosis protein (XIAP) under control of the ubiquitin promoter display reduced hearing loss and cochlear damage induced by acoustic overstimulation (125 dB sound pressure level, 6 h) compared with wild-type (WT) littermates. Hearing status was evaluated using the auditory brainstem response (ABR), whereas cochlear damage was assessed by counts of surviving hair cells (HCs) and spiral ganglion neurons (SGNs) as well as their fibers to HCs. Significantly smaller threshold shifts were found for TG mice than WT littermates. Correspondingly, the TG mice also showed a reduced loss of HCs, SGNs and their fibers to HCs. HC loss was limited to the basal end of the cochlea that detects high frequency sound. In contrast, the ABRs demonstrated a loss of hearing sensitivity across the entire frequency range tested (2-32 kHz) indicating that the hearing loss could not be fully attributed to HC loss alone. The TG mice displayed superior hearing sensitivity over this whole range, suggesting that XIAP overexpression reduces noise-induced hearing loss not only by protecting HCs but also other components of the cochlea.

In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period

“…XIAP overexpression has been demonstrated to prevent neuronal death in models of transient cerebral ischemia and Parkinson's disease (Xu et al, 1999; Ishigaki et al, 2002; Crocker et al, 2003; Trapp et al, 2003). The same ubiquitous XIAP overexpression mice used in this study also exhibit later onset of presbycusis and an insensitivity to noise-induced hearing loss (Wang et al, 2010, 2011). …”

“…Transgenic mice overexpressing XIAP (Wang et al, 2010, 2011) were kind gifts from Dr. Robert G. Korneluk at the Children's Hospital of Eastern Ontario Research Institute (Ottawa, Ontario, Canada). Experiments were performed in C57BL/6J wild-type (WT) mice and in XIAP overexpression mice (Experimental Animal Center, Shanghai Medical College of Fudan University, China).…”

“…X-linked inhibitor of apoptosis protein (XIAP) is the most potent IAP and is a broad-range suppressor of apoptosis that functions by directly inhibiting caspases (Deveraux and Reed, 1999; Deveraux et al, 1999). XIAP is broadly expressed in all human tissues except peripheral blood leukocytes, and XIAP overexpression increases the survival of many cell types upon exposure to a variety of apoptotic triggers (Emamaullee et al, 2005; Zhu et al, 2007; Hu et al, 2010; Plesner et al, 2010; Wang et al, 2010, 2011; Unsain et al, 2013). …”

Using a Concha Electrode to Measure Response Patterns Based on the Amplitudes of Cochlear Microphonic Waveforms Across Acoustic Frequencies in Normal-Hearing Subjects

“…The frequency of 500 Hz can be easily tested in the clinic at a behavioral level (audiogram) and at a neural level (tone burst ABR) (Burkey et al 1998;Chien et al 2008;Vander Werff et al 2009;Wang et al 2011), but it is difficult to test it at the cochlear level. Assessment at the cochlear stage is important because abnormal audiograms or tone burst ABRs do not necessarily indicate an abnormal cochlea, such as in the case of auditory neuropathy.…”

Response Pattern Based on the Amplitude of Ear Canal Recorded Cochlear Microphonic Waveforms across Acoustic Frequencies in Normal Hearing Subjects

“…However, 500 Hz is an important frequency in clinical assessments as this frequency is included in many key hearing tests, such as the turning fork test, the pure tone average test, and the tone burst auditory brainstem response (ABR) test (Burkey, Lippy, Schuring, & Rizer, 1998;Chien et al, 2008;Vander Werff, Prieve, & Georgantas, 2009;Wang et al, 2011).…”