Abstract
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.
Highlights
Sensorineural hearing loss is usually permanent because the human cochlea contains only about 5,000 hair cells (HCs), and these are terminally differentiated cells with very little capacity to regenerate after birth
We show that Apoptosis repressor with caspase recruitment domain (ARC) is expressed in the cochlear HCs and HEI-OC-1 cells and that inhibition of ARC by siRNA significantly increases the cells’ sensitivity to neomycin toxicity
ARC has been reported to be expressed in cochlear spiral ganglion neurons [8]; but we are aware of no report on the expression and function of ARC in inner ear sensory HCs
Summary
Sensorineural hearing loss is usually permanent because the human cochlea contains only about 5,000 hair cells (HCs), and these are terminally differentiated cells with very little capacity to regenerate after birth. The main causes of such hearing loss are noise, aging, and ototoxic drugs, all of which can induce apoptosis in HCs. Aminoglycoside-induced HC damage is one of the major causes of HC death [1], and several studies have reported that aminoglycoside treatment induces the intrinsic apoptosis of HCs through oxidative stress [2,3,4,5,6]. Apoptosis repressor with caspase recruitment domain (ARC) is an important anti-apoptotic protein in both mitochondrial and death receptor apoptosis pathways [7]. The HEI-OC-1 cell line has been used as a cochlear HC-like cell line in many studies, and these cells express several molecular markers of cochlear HCs, including calbindin, calmodulin, math, myosin7a, and prestin [[9,10,11,12]
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