The Role Of ASK1 In Oxygen-induced Retinopathy

Retinopathy of prematurity(ROP)is the leading cause of blindness in children worldwide.The abnormal growth of retinal blood vessels and subsequent retinal detachment caused by the change of oxygen(exposure of infants to high oxygen and then restored to a normal oxygen environment)are considered as the main causes of ROP.The treatment of ROP is mostly aimed at the abnormal growth of blood vessels,such as laser therapy,cryotherapy and the anti-vascular endothelial growth factor agents.However,these treatment methods are associated with tissue injury that leading to partial loss of vision,high recurrence rate and potential side effects.Photoreceptors are a type of nerve cells that are responsible for converting light signals into nerve signals,and ultimately transmitted to the brain.Studies have shown that abnormalities in the structure or function of photoreceptor cilium could lead to photoreceptor degeneration and even visual loss.However,it is unclear whether photoreceptor cilium could also participate in the degeneration of ROP.The mouse model of oxygen-induced retinopathy(OIR)is a well-established model to study ROP.In this study,we used this model to clarify the pathogenesis and molecular mechanisms of ROP,and explore a new and effective therapy for preventing ROP.Here,using OIR mouse model for ROP,through a series of experiments such as immunofluorescence staining,we found that the length of OS in OIR mice was significantly shorter than the control group,and the photoreceptor cilium were significantly reduced.Further study showed that HDAC6 was up-regulated.Through the next step of exploring the mechanism,we found that apoptosis signal-regulating kinase 1(ASK1) interacted with HDAC6.Oxygen changes induced the activation of ASK1 and the collection of HDAC6 on the photoreceptor cilium.Leading to photoreceptor cilium disassembly mediated by HDAC6.More importantly,using small molecule inhibitors targeting ASK1 could effectively protect the photoreceptor degeneration caused by oxygen changes.These findings clarify the pathological function and molecular mechanism of ASK1 mediated photoreceptor cilium disassembly in ROP,and demonstrate a potential value of the inhibitors targeting ASK1 to prevent ROP.