Heat shock inhibits both aminoglycoside- and cisplatin-induced sensory hair cell death
Heat shock inhibits both aminoglycoside- and cisplatin-induced sensory hair cell death
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DOI：
10.1007/s10162-006-0043-x
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发表时间：
2006-09-01
影响因子：
2.4
通讯作者：
Brandon, Carlene S.
中科院分区：
文献类型：
--
作者：
Cunningham, Lisa L.;Brandon, Carlene S.
人类听力和平衡障碍通常归因于内耳感觉毛细胞的死亡。这些细胞对噪声暴露、衰老和一些治疗药物诱导的死亡高度敏感。两大类耳毒性药物是氨基糖苷类抗生素和顺铂。暴露于这些药物导致毛细胞死亡，这是由特定的凋亡蛋白，包括半胱天冬酶的激活介导的。热休克蛋白（HSP）在细胞应激反应中的诱导是一种普遍存在且高度保守的反应，其可以通过抑制凋亡蛋白来显著抑制某些系统中的凋亡。热休克蛋白的诱导发生在毛细胞响应于各种刺激。由于热休克蛋白可以直接抑制细胞凋亡，我们推测热休克可能会抑制暴露于耳毒性药物的毛细胞凋亡。为了验证这一假设，我们开发了一种体外诱导成年小鼠椭圆囊中HSP表达的方法。体外热休克可靠地产生HSP-70 mRNA和蛋白的稳健上调，以及HSP-90和HSP-27的更适度上调。热休克不会导致毛细胞死亡。热休克有显着的保护作用，对氨基糖苷类和顺铂诱导的毛细胞死亡的椭圆囊制备在体外。这些数据表明热休克可以抑制耳毒性药物诱导的毛细胞死亡，并且椭圆囊制剂可以用于检查这种保护作用的分子机制。
Human hearing and balance impairments are often attributable to the death of sensory hair cells in the inner ear. These cells are hypersensitive to death induced by noise exposure, aging, and some therapeutic drugs. Two major classes of ototoxic drugs are the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to these drugs leads to hair cell death that is mediated by the activation of specific apoptotic proteins, including caspases. The induction of heat shock proteins (HSPs) in response to cellular stress is a ubiquitous and highly conserved response that can significantly inhibit apoptosis in some systems by inhibiting apoptotic proteins. Induction of HSPs occurs in hair cells in response to a variety of stimuli. Given that HSPs can directly inhibit apoptosis, we hypothesized that heat shock may inhibit apoptosis in hair cells exposed to ototoxic drugs. To test this hypothesis, we developed a method for inducing HSP expression in the adult mouse utricle in vitro. In vitro heat shock reliably produces a robust up-regulation of HSP-70 mRNA and protein, as well as more modest up-regulation of HSP-90 and HSP-27. The heat shock does not result in death of hair cells. Heat shock has a significant protective effect against both aminoglycoside- and cisplatin-induced hair cell death in the utricle preparation in vitro. These data indicate that heat shock can inhibit ototoxic drug-induced hair cell death, and that the utricle preparation can be used to examine the molecular mechanism(s) underlyring this protective effect.