Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 79, Issue 2, Pages -Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-04029-9
Keywords
Aminoglycosides; Hair cells; Apoptosis; Protection; Hippo; YAP signaling pathway; Sensorineural hearing loss (SNHL)
Categories
Funding
- National Key R&D Program of China [2021YFA1101300, 2020YFA0112503]
- Strategic Priority Research Program of the Chinese Academy of Science [XDA16010303]
- National Natural Science Foundation of China [82030029, 81970884, 81900941, 81900944, 81970882, 81870721, 81771019, 81700913]
- Natural Science Foundation of Jiangsu Province [BE2019711, BK20190121]
- Science and Technology Department of Sichuan Province [2021YFS0371]
- Shenzhen Fundamental Research Program [JCYJ20190814093401920, JCYJ20210324125608022]
- Open Research Fund of State Key Laboratory of Genetic Engineering, Fudan University [SKLGE-2109]
- Nanjing Medical Science and technique Development Foundation [QRX17051]
- Boehringer Ingelheim Pharma GmbH
- Project of Invigorating Health Care Through Science, Technology and Education [ZDXKB2016015]
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The Hippo/Yes-associated protein (YAP) signaling pathway plays an important role in protecting cochlear hair cells from damage caused by aminoglycosides. It does so by inhibiting cell apoptosis and reducing the accumulation of reactive oxygen species (ROS).
The Hippo/Yes-associated protein (YAP) signaling pathway has been shown to be able to maintain organ size and homeostasis by regulating cell proliferation, differentiation, and apoptosis. The abuse of aminoglycosides is one of the main causes of sensorineural hearing loss (SSNHL). However, the role of the Hippo/YAP signaling pathway in cochlear hair cell (HC) damage protection in the auditory field is still unclear. In this study, we used the YAP agonist XMU-MP-1 (XMU) and the inhibitor Verteporfin (VP) to regulate the Hippo/YAP signaling pathway in vitro. We showed that YAP overexpression reduced neomycin-induced HC loss, while downregulated YAP expression increased HC vulnerability after neomycin exposure in vitro. We next found that activation of YAP expression inhibited C-Abl-mediated cell apoptosis, which led to reduced HC loss. Many previous studies have reported that the level of reactive oxygen species (ROS) is significantly increased in cochlear HCs after neomycin exposure. In our study, we also found that YAP overexpression significantly decreased ROS accumulation, while downregulation of YAP expression increased ROS accumulation. In summary, our results demonstrate that the Hippo/YAP signaling pathway plays an important role in reducing HC injury and maintaining auditory function after aminoglycoside exposure. YAP overexpression could protect against neomycin-induced HC loss by inhibiting C-Abl-mediated cell apoptosis and decreasing ROS accumulation, suggesting that YAP could be a novel therapeutic target for aminoglycosides-induced sensorineural hearing loss in the clinic.
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