Hypoxia-inducible factor 1-alpha target protein up-regulation in Hypoxic cochlear neurons is associate with aged-related hearing loss in C57BL/6 mice

Abstract

Molecular mechanisms underlining hypoxia-induced aged-hearing loss were studied. 3-months C57BL/6 mice were subjected to four weeks of hypoxia (10% 0 2 ), whereas, controls were kept under normoxic condition for up to six months. Auditory function was explored by CAP and Preyer's reflex measurements and correlated with histological analysis of the cochlea. The presence of oxidative damage, HIF-1 responsive target genes regulation involved in cell death, inflammation and neovascularization were assessed by immunofluorescence analysis. Hypoxia was associated to severe hearing loss at 4-8 and 16 KHz and degeneration of the cochlea, with significant cell loss (30%) in the spiral ganglion, the lateral wall, and the hair cells with a basal-apical alteration gradient. This was correlated with ROS formation and HIF-1a overexpression. Cochlear degeneration was due to apoptosis via activated caspase-3, P53, Bax and Bcl-2 protein differential expression in spiral ganglion, modiolus and spiral ligament. On the other hand, Hsp70, NF-kB transcription factor pathway and inflammatory mediators (caspase-1 and TNF-a) were induced in the stria vascularis. Furthermore, a phenomenon of neovascularization was observed with significant thickening of stria vascularis and increased expression of VEGF. In total, we demonstrated that the tandem-HIF-ROS is responsible for the caspase-3 and Bax-mediated apoptosis via P53 protein accumulation in the cochlear neurons, while inflammatory response mediated by Hsp70 stress protein and NF-kB transcription factor generating a neovascularization phenomenon occurred in stria vascularis.

Changes in the Cochlear Vasculature and Vascular Endothelial Growth Factor and Its Receptors in the Aging C57 Mouse Cochlea

“…It has long been known that cochlear hypoxia due to reductions of cochlear blood flow occurs with age [15, 16] and that temporary hypoxia can result in reversible hearing loss [17]. Recent work has demonstrated up-regulation of VEGF occurs in response to cochlear hypoxia and as previously noted, with age [8, 9, 18]. …”