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首页> 外文期刊>Experimental Gerontology >Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea.
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Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea.

机译：CD / 1小鼠中与年龄有关的听力损失与耳蜗中的ROS形成和HIF目标蛋白上调有关。

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摘要

Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. In this study, we explored auditory function of cd/1 mice at the age of 4, 12 and 24 weeks and correlated it with the presence of oxidative damage in the cochlea, and cochlear HIF-1 responsive target genes regulation, involved in pathways promoting inflammation such as tumor necrosis factor (TNF-alpha), or cell death with the p53 protein, Bax protein and surviving factors with insulin-like growth factor-1 (IGF-1). After implantation of electrodes for auditory nerve acoustic thresholds measurements, we analyzed every cochlea. First, we confirmed that the cd/1 mice presented a characteristic profile of ARHL starting at 12 weeks of age. Then, according to our previous report [Riva, C., Longuet, M., Lucciano, M., Magnan, J., Lavieille, J.P., 2005. Implication of mitochondrial apoptosis in neural degeneration in a murin model for presbyacusis. Rev. Laryngol. Otol. Rhinol. 126 (2), 67-74], we noticed many alterations in the cochlea. Histologically, at 4 weeks, intensive HIF-1alpha expression was detected in the cochlea followed by ROS formation at 12 weeks, which may lead to cochlear degeneration and induction the onset of ARHL in the cd/1 mice model. In the cochlea, while the inner and the outer hair cells remained intact at 4 and 12 weeks, the spiral ganglion was more altered. Moreover, the Schwann cells of the spiral ganglion seemed to be more vulnerable to free radical damage than the neurons and degenerated more rapidly. The mechanisms of degeneration in the spiral ganglion involved a caspase-3 and Bax mediated-apoptosis via p53 protein accumulation. Since oxygen radicals are required for the post-translational stabilization of HIF-1alpha during hypoxia, the tandem " HIF-ROS " induced multiple reactions within the cochlea, like a strong inflammatory response with increased expression of TNF-alpha, and inhibition of neuronal protection mechanisms with repression of IGF-1.
机译：衰老的病理学，特别是神经感觉器官的病理学代表了重要的健康问题。预期寿命的提高必然导致人口中与年龄有关的听力损失（ARHL）的频率迅速增加。有许多因素促成这一过程，包括血管特征的改变，缺氧/缺血，遗传突变和活性氧的产生。我们对了解ARHL小鼠模型cd / 1小鼠的耳蜗变性所涉及的机制感兴趣。由于在人类中，缺氧/缺血是内耳疾病的重要致病因素，因此研究了耳蜗中HIF-1活性的调节，耳蜗中自由基氧的存在及其随后对细胞信号级联反应的干扰。在这项研究中，我们探讨了cd / 1小鼠在4、12和24周龄时的听觉功能，并将其与耳蜗中氧化损伤的存在以及耳蜗HIF-1反应性靶基因的调节相关，参与了促进途径炎症，例如肿瘤坏死因子（TNF-alpha）或p53蛋白，Bax蛋白引起的细胞死亡以及胰岛素样生长因子1（IGF-1）的存活因子。植入电极用于听神经声学阈值测量后，我们分析了每个耳蜗。首先，我们确认cd / 1小鼠从12周龄开始呈现ARHL的特征性特征。然后，根据我们以前的报告[Riva，C.，Longuet，M.，Lucciano，M.，Magnan，J.，Lavieille，J.P.，2005年。线粒体细胞凋亡在老年痴呆症的murin模型中对神经变性的影响。 Laryngol牧师。耳语犀牛126（2），67-74]，我们注意到耳蜗有许多改变。在组织学上，在第4周时，在耳蜗中检测到大量的HIF-1α表达，然后在第12周时形成ROS，这可能导致耳蜗变性并诱导cd / 1小鼠模型中ARHL的发作。在耳蜗中，内，外毛细胞在第4周和第12周保持完整，而螺旋神经节的变化更大。此外，螺旋神经节的雪旺氏细胞似乎比神经元更容易受到自由基的破坏，并且退化得更快。螺旋神经节的变性机制涉及caspase-3和Bax通过p53蛋白积累介导的细胞凋亡。由于缺氧期间HIF-1alpha的翻译后稳定需要氧自由基，因此串联的“ HIF-ROS”在耳蜗内引起多种反应，例如强烈的炎症反应和TNF-alpha的表达增加以及神经元保护的抑制抑制IGF-1的机制。

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