Inhibition Of ARC Decreases The Survival Of HEI-OC-1 Cells After Neomycin Damage In Vitro

Hearing loss is a common sensory disorder mainly caused by the loss of hair cells(HCs).Noise,aging,and ototoxic drugs can all induce apoptosis in HCs.Apoptosis repressor with caspase recruitment domain(ARC)is a key factor in apoptosis that inhibits both intrinsic and extrinsic apoptosis pathways;however,there have been no reports on the role of ARC in HC loss in the inner ear.In this study,we used House Ear Institute Organ of Corti 1(HEI-OC-1)cells,which is a cochlear hair-cell-like cell line,to investigate the role of ARC in aminoglycoside-induced HC loss.ARC was expressed in the cochlear HCs as well as in the HEI-OC-1 cells,but not in the supporting cells,and the expression level of ARC in HCs was decreased after neomycin injury in both cochlear HCs and HEI-OC-1 cells,suggesting that reduced levels of ARC might correlate with neomycin-induced HC loss.We inhibited ARC expression using siRNA and found that this significantly increased the sensitivity of HEI-OC-1 cells to neomycin toxicity.Finally,we found that ARC inhibition increased the expression of pro-apoptotic factors,decreased the mitochondrial membrane potential,and increased the level of reactive oxygen species(ROS)after neomycin injury,suggesting that ARC inhibits cell death and apoptosis in HEI-OC-1 cells by controlling mitochondrial function and ROS accumulation.Thus the endogenous anti-apoptotic factor ARC might be a new therapeutic target for the prevention of aminoglycoside-induced HC loss.