Abstract
Objective To investigate the expression of early growth response protein-1 (Egr-1)in the retina of myopic mice induced by a low-frequency flickering light (FL) and its underlying regulation mechanism in the extracellular matrix remodeling pathway.Methods C57BL/6 mice (n=100) 28 days of age were randomly assigned to two groups:a normal control (n=50) and an FL stimulation group (n=50).The FL group were raised under illumination with a duty cycle of 50％ at a flash rate of 2 Hz.Refractive state and axial length (AL) of the right eyes were measured by a murine-specific eccentric infrared photorefraction and A-scan ultrasonography,respectively.The data were collected at pre-treatment and at 1 hour,1 day,1 week,2 weeks,and after 1 week of recovery.The FL group were removed after 2 weeks of FL stimulation,and the mice were returned to normal light conditions as in the control group.Retinal tissue was collected at each time point to measure the levels of mRNA in Egr-1,membrane type 1 matrix metalloproteinase (MT1-MMP),matrix metalloproteinase-2 (MMP-2),and the tissue inhibitor of metalloproteinase-2 (TIMP-2) by quantitative real-time PCR.In addition,the level and location of Egr-1 and MT1-MMP proteins were analyzed by Western Blot,immunohistochemistry and immunofluorescence.A one-way analysis of variance was used to compare the data from the FL and control groups.An independent samples t test was used to compare indexes between the FL group and control group.Results After 2 weeks of FL stimulation,refraction became more myopic compared with the control group (0.32±0.14 D vs.3.42±0.31 D,t=29.08,P＜0.01),and AL increased faster (2.97±0.01 mm vs.2.93±0.01 mm,t=6.914,P＜0.01).During the FL treatment phase,Egr-1 mRNA and the protein levels in the treated eyes were rapidly down-regulated after 1 hour,and persistently down-regulated in the retina during treatment.MT1-MMP and MMP-2 levels were up-regulated while TIMP-2 levels were down-regulated in the treated eyes only at time points of 1 or 2 weeks of treatment.During the recovery phase,after 1 week,Egr-1 and TIMP-2 were up-regulated,while MT1-MMP and MMP-2 were down-regulated.Egr-1 and MT1-MMP or MMP-2 were negatively correlated.Immunofluorescence double staining showed Egr-1 immunoreactivity co-localization with MT1-MMP in retinal ganglion cells.Conclusion Retinal Egr-1 may have an effect on the activation of MMP-2 by regulating the expression of MT1-MMP in FL-induced mice myopia and during the recovery process. Key words: Myopia; Egr-1; Flickering light; Matrix metalloproteinases,membrane-associated; Matrix metalloproteinase 2; Models,animal
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