Deficiency of sphingomyelin synthase-1 but not sphingomyelin synthase-2 causes hearing impairments in mice
Deficiency of sphingomyelin synthase-1 but not sphingomyelin synthase-2 causes hearing impairments in mice
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DOI：
10.1113/jphysiol.2012.235846
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发表时间：
2012-08-01
影响因子：
5.5
通讯作者：
Song, Wen-Jie
中科院分区：
文献类型：
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作者：
Lu, Mei-Hong;Takemoto, Makoto;Song, Wen-Jie
鞘磷脂(SM)是一种鞘磷脂，被认为是质膜的结构成分，并参与信号转导。SM代谢在听力过程中的作用仍存在争议。在这里，我们研究了SM合成酶(SM Synthase，SMS)，它被细分为SMS1和SMS2家族成员，在听觉功能中的作用。听性脑干反应(ABR)的测量显示，SMS1(-/-)小鼠在低频范围(4-16 kHz)有听力障碍。作为这种损伤的可能机制，我们发现这些小鼠的血管纹(SV)表现出萎缩和边缘细胞的紊乱。因此，SMS1(-/-)小鼠表现出明显较小的耳蜗内电位(EP)。作为EP减少的可能机制，我们在SMS1(-/-)小鼠的SV中发现了表达模式的改变和KCNQ1通道蛋白水平的降低。这些小鼠的失真产物耳声发射水平也有所降低。SMS1(-/-)小鼠耳蜗尖、基转区SV萎缩、KCNQ1表达和外毛细胞密度的定量比较显示没有位置依赖性，但顶区比基底区有更多的巨噬细胞侵入SV，提示耳蜗区位置依赖性氧化应激在SMS1(-/-)小鼠产生频率依赖性听力损失中的作用。在SMS1(-/-)小鼠中，ABR阈值升高、EPs减少和KCNQ1异常表达模式都被发现随着年龄的增长而递增。然而，缺乏SMS2的小鼠既没有表现出可检测到的听力损失，也没有表现出EPs的变化。综上所述，我们的结果表明，SMS1(-/-)小鼠存在听力障碍，而SMS2(-/-)小鼠则没有。在SMS1(-/-)小鼠中，SV的缺陷和随后的EPs的减少以及毛细胞功能障碍可能至少部分地解释了听力损伤。
Sphingomyelin (SM) is a sphingolipid reported to function as a structural component of plasma membranes and to participate in signal transduction. The role of SM metabolism in the process of hearing remains controversial. Here, we examined the role of SM synthase (SMS), which is subcategorized into the family members SMS1 and SMS2, in auditory function. Measurements of auditory brainstem response (ABR) revealed hearing impairment in SMS1(-/-) mice in a low frequency range (4-16 kHz). As a possiblemechanism of this impairment, we found that the stria vascularis (SV) in these mice exhibited atrophy and disorganized marginal cells. Consequently, SMS1(-/-) mice exhibited significantly smaller endocochlear potentials (EPs). As a possible mechanism for EP reduction, we found altered expression patterns and a reduced level of KCNQ1 channel protein in the SV of SMS1(-/-) mice. These mice also exhibited reduced levels of distortion product otoacoustic emissions. Quantitative comparison of the SV atrophy, KCNQ1 expression, and outer hair cell density at the cochlear apical and basal turns revealed no location dependence, but more macrophage invasion into the SV was observed in the apical region than the basal region, suggesting a role of cochlear location-dependent oxidative stress in producing the frequency dependence of hearing loss in SMS1(-/-) mice. Elevated ABR thresholds, decreased EPs, and abnormal KCNQ1 expression patterns in SMS1(-/-) mice were all found to be progressive with age. Mice lacking SMS2, however, exhibited neither detectable hearing loss nor changes in their EPs. Taken together, our results suggest that hearing impairments occur in SMS1(-/-) but not SMS2(-/-) mice. Defects in the SV with subsequent reductions in EPs together with hair cell dysfunction may account, at least partially, for hearing impairments in SMS1(-/-) mice.