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  3. CFTR potentiator ivacaftor protects against noise-induced hair cell loss by increasing Nrf2 and reducing oxidative stress

CFTR potentiator ivacaftor protects against noise-induced hair cell loss by increasing Nrf2 and reducing oxidative stress

  • Biomed Pharmacother. 2023 Aug 30;166:115399. doi: 10.1016/j.biopha.2023.115399.
Fan Wu 1,  Rui Hu 2,  Xueping Huang 3,  Jintao Lou 3,  Ziyi Cai 3,  Guisheng Chen 3,  Wenji Zhao 3,  Hao Xiong 3,  Su-Hua Sha 4,  Yiqing Zheng 5
Affiliations

Affiliations

  • 1 Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, China; Department of Pathology and Laboratory Medicine, The Medical University of South Carolina, Charleston, SC, USA.
  • 2 Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Shenshan Medical Center, Memorial Hospital of Sun Yat-sen University, Shanwei, Guangdong, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, China.
  • 3 Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, China.
  • 4 Department of Pathology and Laboratory Medicine, The Medical University of South Carolina, Charleston, SC, USA. Electronic address: shasu@musc.edu.
  • 5 Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Shenshan Medical Center, Memorial Hospital of Sun Yat-sen University, Shanwei, Guangdong, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: zhengyiq@mail.sysu.edu.cn.
PMID: 37657258 DOI: 10.1016/j.biopha.2023.115399
Abstract

Over-production of Reactive Oxygen Species (ROS) in the inner ear can be triggered by a variety of pathological events identified in animal models after traumatic noise exposure. Our previous research found that inhibition of the AMP-activated protein kinase alpha subunit (AMPKα) protects against noise-induced cochlear hair cell loss and hearing loss by reducing ROS accumulation. However, the molecular pathway through which AMPKα exerts its antioxidative effect is still unclear. In this study, we have investigated a potential target of AMPKα and ROS, cystic fibrosis transmembrane conductance regulator (CFTR), and the protective effect against noise-induced hair cell loss of an FDA-approved CFTR potentiator, ivacaftor, in FVB/NJ mice, mouse explant cultures, and HEI-OC1 cells. We found that noise exposure increases phosphorylation of CFTR at serine 737 (p-CFTR, S737), which reduces wildtype CFTR function, resulting in oxidative stress in cochlear sensory hair cells. Pretreatment with a single dose of ivacaftor maintains CFTR function by preventing noise-increased p-CFTR (S737). Furthermore, ivacaftor treatment increases nuclear factor E2-related factor 2 (Nrf2) expression, diminishes ROS formation, and attenuates noise-induced hair cell loss and hearing loss. Additionally, inhibition of noise-induced AMPKα activation by compound C also diminishes p-CFTR (S737) expression. In line with these in-vivo results, administration of hydrogen peroxide to cochlear explants or HEI-OC1 cells increases p-CFTR (S737) expression and induces sensory hair cell or HEI-OC1 cell damage, while application of ivacaftor halts these effects. Although ivacaftor increases Nrf2 expression and reduces ROS accumulation, cotreatment with ML385, an Nrf2 inhibitor, abolishes the protective effects of ivacaftor against hydrogen-peroxide-induced HEI-OC1 cell death. Our results indicate that noise-induced sensory hair cell damage is associated with p-CFTR. Ivacaftor has potential for treatment of noise-induced hearing loss by maintaining CFTR function and increasing Nrf2 expression for support of redox homeostasis in sensory hair cells.

Keywords

Activation of AMPKα; Cystic fibrosis transmembrane conductance regulator ivacaftor; Noise-induced hearing loss; Nuclear factor E2-related factor 2; Reactive oxygen species.

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