Estrogen Ameliorates Auditory Function of Middle-Aging Mice by Decreasing MMP-9 via ERK Pathway
DENG Shuang1,2#, YU Meng1,3#, WANG Yanping1, YU Miao2, HU Yicheng1, SI Junqiang2, LI Li1, JIA Jinjing1*
Previous studies have focused on the protective effect of estrogen on auditory hair cells and spiral ganglion cells. However, whether estrogen could protect the cochlear BLB (blood-labyrinth barrier) is largely unknown. Here, the effect of estrogen on the permeability of the stria vascular BLB in the middle-aging cochlea was examined. Female 12-month-old C57BL/6J mice (middle-aging) were used as an animal model of presbycusis, subjected to OVX (ovariectomy) and then subcutaneously injected with E2 (17beta-estradiol). An in vitro co-culture model of BLB primary pericytes and endothelial cells treated with D-gal (D-galactose), an aging inducer, was established to study the protective mechanisms of estrogen. Compared to that of 3-month-old mice (3m group, n=12), the hearing threshold and the permeability of BLB in middle-aging mice (12m group, n=12) were significantly increased, which were further aggravated in middle-aging mice subjected to OVX (12mOVX group, n=12) and then reversed by E2 treatment (12mOVX+E2 group, n=12). Immunohistochemistry and immunofluorescence staining further demonstrated that E2 treatment markedly up-regulated the expression of tight junction proteins (VE-cad and ZO-1) and decreased the expression of MMP-9 (matrix metalloproteinase-9) in the BLB of 12mOVX+E2 group compared to that in 12mOVX group. E2 treatment significantly restored the changes of MMP-9, VE-cad and ZO-1 induced by D-gal. These effects were partially inhibited by pretreatment of U0126, an inhibitor of ERK (extracellular signal-regulated kinase). In conclusion, estrogen ameliorates auditory function by decreasing MMP-9 via ERK pathway, suggesting that estrogen may be a promising candidate for the prevention and treatment of presbycusis.
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