Abstract

To investigate the role of the exchange protein directly activated by cAMP (Epac) signaling pathway in inner ear hair cell damage and apoptosis after noise exposure, we analyzed the expression level of Epac1 in a rat model of noise-induced hearing loss (NIHL), based on rat exposure to a 4-kHz and 106-dB sound pressure level (SPL) for 8 h. Loss of outer hair cells (OHCs), mitochondrial lesions, and hearing loss were examined after treatment with the Epac agonist, 8-CPT, or the Epac inhibitor, ESI-09. The effects of 8-CPT and ESI-09 on cell proliferation and apoptosis were examined by CCK-8 assays, holographic microscopy imaging, and Annexin-V FITC/PI staining in HEI-OC1 cells. The effects of 8-CPT and ESI-09 on Ca 2+ entry were evaluated by confocal Ca 2+ fluorescence measurement. We found that the expression level of Epac1 was significantly increased in the cochlear tissue after noise exposure. In NIHL rats, 8-CPT increased the loss of OHCs, mitochondrial lesions, and hearing loss compared to control rats, while ESI-09 produced the opposite effects. Oligomycin was used to induce HEI-OC1 cell damage in vitro . In HEI-OC1 cells treated with oligomycin, 8-CPT and ESI-09 increased and reduced cell apoptosis, respectively. Moreover, 8-CPT promoted Ca 2+ uptake in HEI-OC1 cells, while ESI-09 inhibited this process. In conclusion, our data provide strong evidence that the Epac1 signaling pathway mediates early pathological damage in NIHL, and that Epac1 inhibition protects from NIHL, identifying Epac1 as a new potential therapeutic target for NIHL.