Extracellular ATP accelerates cell death and decreases tight junction protein ZO-1 in hypoxic cochlear strial marginal cells in neonatal rats

In the cochlea, extracellular ATP (eATP) plays an important role in both physiological and pathological processes, but its role in the hypoxic cochlea remains unclear. The present study aims to investigate the relationship between eATP and hypoxic marginal cells (MCs) in the stria vascularis in cochlea. Combining various methodologies, we found that eATP accelerates cell death and decreases tight junction protein zonula occludens-1 (ZO-1) in hypoxic MCs. Flow cytometry and western blot analyses revealed an increase in apoptosis levels and suppression of autophagy, indicating that eATP causes additional cell death by increasing the apoptosis of hypoxic MCs. Given that autophagy inhibits apoptosis to protect MCs under hypoxia, apoptosis is probably enchanced by suppressing autophagy. Interleukin-33(IL-33)/suppression of tumorigenicity-2(ST-2)/matrix metalloprotein 9(MMP9) pathway activation was also observed during the process. Further experiments involving the use of additional IL-33 protein and an MMP9 inhibitor indicated that this pathway is responsible for the damage to the ZO-1 protein in hypoxic MCs. Our study revealed an adverse effect of eATP on the survival and ZO-1 protein expression of hypoxic MCs, as well as the underlying mechanism.