Hearing vulnerability after noise exposure in a mouse model of reactive oxygen species overproduction
Hearing vulnerability after noise exposure in a mouse model of reactive oxygen species overproduction
复制标题
DOI：
10.1111/jnc.14451
复制
发表时间：
2018-08-01
影响因子：
4.7
通讯作者：
Ueyama, Takehiko
中科院分区：
文献类型：
--
作者：
Morioka, Shigefumi;Sakaguchi, Hirofumi;Ueyama, Takehiko
先前的研究令人信服地表明，活性氧（ROS）参与了几种主要类型的感音神经性听力损失的发展，例如噪声性听力损失（NIHL）、药物性听力损失和年龄相关性听力损失。然而，在这些病理过程中由ROS诱导的潜在分子机制仍不清楚。为了解决这个问题，我们通过培育一种表达人NADPH氧化酶4（NOX4，NOX4转基因小鼠）的转基因小鼠品系建立了一个体内ROS过量产生的模型，NADPH氧化酶4是一种组成型活性的产ROS酶，不需要刺激或激活剂。在NOX4转基因小鼠的内耳耳蜗中检测到ROS过量产生，但它们在基线条件下表现出正常的听力功能。然而，在暴露于强烈噪声时，它们表现出听力功能的脆弱性，尤其是在高频声音下，同时伴有耳蜗外毛细胞（OHCs）的损失。通过使用抗氧化剂Tempol治疗，听力功能丧失和外毛细胞损失的脆弱性得到了挽救。此外，我们发现，在使用HEK293细胞的模型中，包括过氧化氢处理以及稳定和瞬时表达NOX4的细胞中，热休克蛋白47（HSP47）的蛋白水平升高。而且，在NOX4转基因小鼠的耳蜗和心脏中都观察到Hsp47水平的上调。因此，抗氧化治疗是治疗噪声性听力损失的一种有前景的方法。Hsp47可能是一种内源性抗氧化因子，在体内补偿慢性ROS过度暴露，并对抗与ROS相关的听力损失。
Previous studies have convincingly argued that reactive oxygen species (ROS) contribute to the development of several major types of sensorineural hearing loss, such as noise-induced hearing loss (NIHL), drug-induced hearing loss, and age-related hearing loss. However, the underlying molecular mechanisms induced by ROS in these pathologies remain unclear. To resolve this issue, we established an invivo model of ROS overproduction by generating a transgenic (TG) mouse line expressing the human NADPH oxidase 4 (NOX4, NOX4-TG mice), which is a constitutively active ROS-producing enzyme that does not require stimulation or an activator. Overproduction of ROS was detected at the cochlea of the inner ear in NOX4-TG mice, but they showed normal hearing function under baseline conditions. However, they demonstrated hearing function vulnerability, especially at high-frequency sounds, upon exposure to intense noise, which was accompanied by loss of cochlear outer hair cells (OHCs). The vulnerability to loss of hearing function and OHCs was rescued by treatment with the antioxidant Tempol. Additionally, we found increased protein levels of the heat-shock protein 47 (HSP47) in models using HEK293 cells, including H2O2 treatment and cells with stable and transient expression of NOX4. Furthermore, the up-regulated levels of Hsp47 were observed in both the cochlea and heart of NOX4-TG mice. Thus, antioxidant therapy is a promising approach for the treatment of NIHL. Hsp47 may be an endogenous antioxidant factor, compensating for the chronic ROS overexposure invivo, and counteracting ROS-related hearing loss.