cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function
cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function
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DOI：
10.1038/nm.2634
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发表时间：
2012-02-01
期刊：
影响因子：
82.9
通讯作者：
Ruettiger, Lukas
中科院分区：
文献类型：
--
作者：
Jaumann, Mirko;Dettling, Juliane;Ruettiger, Lukas
噪声性听力损失（NIHL）是一种全球性的健康危害，具有相当大的病理生理和社会后果，且尚无有效的治疗方法。在心脏、肺和其他器官中，环磷酸鸟苷 (cGMP) 促进响应创伤事件的保护过程。因此，我们分析了编码 cGMP 依赖性蛋白激酶 1 型 (Prkg1) 基因的小鼠中的 NIHL，发现与没有删除的小鼠相比，这些小鼠更容易患 NIHL，而且从 NIHL 中恢复的能力也明显较差。 Prkg1在野生型小鼠内耳的感觉细胞和神经元中表达，其表达与cGMP水解磷酸二酯酶5（Pde5）的表达谱部分重叠。用 Pde5 抑制剂伐地那非治疗大鼠和野生型小鼠几乎完全预防了 NIHL，并引起毛细胞和螺旋神经节中 Prkg1 依赖性的聚（ADP-核糖）上调，表明内源性保护性 cGMP-Prkg1 信号通路最终导致聚（ADP-核糖）聚合酶的激活。这些数据表明伐地那非或相关药物可能是治疗 NIHL 的候选药物。
Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type 1 (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.