Is S-nitrosylation of Cochlear Proteins a Critical Factor in Cisplatin-Induced Ototoxicity?
Is S-nitrosylation of Cochlear Proteins a Critical Factor in Cisplatin-Induced Ototoxicity?
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DOI：
10.1089/ars.2012.4656
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发表时间：
2012-10-01
影响因子：
6.6
通讯作者：
Hinduja, Sneha
中科院分区：
文献类型：
--
作者：
Jamesdaniel, Samson;Manohar, Senthilvelan;Hinduja, Sneha
S - 亚硝基化是一种对氧化还原敏感的蛋白质修饰，它是一种高度特异性但可逆的机制，可调节多种信号转导级联反应。氧化应激在抗肿瘤药物顺铂的耳毒性作用中起因果作用。尽管有新出现的证据表明氮氧化应激是顺铂毒性的一个关键因素，但耳蜗蛋白质S - 亚硝基化在顺铂耳毒性中的重要性仍有待了解。在本研究中，16毫克/千克剂量的顺铂在处理后3天导致Wistar大鼠畸变产物耳声发射振幅发生显著变化，畸变产物耳声发射是一种衡量外毛细胞活动的指标。这些耳毒性效应伴随着至少三种耳蜗蛋白质的S - 亚硝基化显著增加。这些S - 亚硝基化蛋白质的生物学意义通过它们在柯蒂氏器、血管纹和螺旋神经节中的免疫定位得以表明，这些部位是已知的顺铂毒性的耳蜗靶点。此外，与特洛克斯（一种过氧亚硝酸盐抑制剂）共同处理可减轻顺铂诱导的耳蜗蛋白质S - 亚硝基化，并防止相关的听力损失。顺铂诱导的内耳蛋白质S - 亚硝基化、它们在耳蜗中的敏感定位以及它们与顺铂诱导的听力损失的潜在关联表明，耳蜗蛋白质的S - 亚硝基化可能在介导顺铂耳毒性中起关键作用。《抗氧化剂与氧化还原信号》17，929 - 933页。
S-nitrosylation is a redox-sensitive protein modification, which is a highly specific, but reversible mechanism that regulates several signal transduction cascades. Oxidative stress plays a causal role in the ototoxic effects of an anti-neoplastic drug, cisplatin. Despite emerging evidence implicating nitroxidative stress as a critical factor in cisplatin toxicity, the significance of the cochlear protein S-nitrosylation in cisplatin ototoxicity is yet to be understood. In the present study, a 16-mg/kg dose of cisplatin, induced a significant shift in the amplitudes of distortion product otoacoustic emissions, a measure of outer hair cell activity, in Wistar rats, 3 days post-treatment. These ototoxic effects were accompanied by significant increases in the S-nitrosylation of at least three cochlear proteins. Biological significance of these S-nitrosylated proteins was indicated by their immunolocalization in organ of Corti, stria vascularis, and spiral ganglions, which are known cochlear targets of cisplatin toxicity. In addition, co-treatment with Trolox, an inhibitor of peroxynitrite, attenuated cisplatin-induced S-nitrosylation of cochlear proteins and prevented the associated hearing loss. The cisplatin-induced S-nitrosylation of inner ear proteins, their sensitive cochlear localization, and their potential association with cisplatin-induced hearing loss suggests that S-nitrosylation of cochlear proteins might play a crucial role in mediating cisplatin ototoxicity. Antioxid. Redox Signal. 17, 929-933.