MicroRNA-143 plays a protective role in ischemia-induced retinal neovascularization

Abstract

Purpose : Retinal neovascularization is a severe complication of retinopathy of prematurity and proliferative diabetic retinopathy. MicroRNAs (miRNAs) are master regulators of gene expression that play important roles in retinal neovascularization. Here, we defined the expression profile of retinal miRNA and investigated the role of miRNA-143 in a rat model of oxygen-induced retinopathy (OIR).

Methods : Rat pups were subjected to cyclic hyperoxia or normoxia (control) for 14 days, after which retinal RNA was isolated for miRNA profiling by next-generation sequencing (miRNA-Seq). To validate the identified miRNAs, synthetic miRNA mimics were administrated intravitreally to rats with OIR at postnatal day (P) 14. Retinal vascular remodelling was assessed 4 days later at P18. The role of miRNA-143 and its molecular network mediating retinal neovascularization were analyzed by RNA-Seq and bioinformatics analysis. A downstream target of miRNA-143 was inhibited as a potential treatment for neovascularization in OIR rat.

Results : Four miRNAs, miR-143-3p, miR-126-3p, miR-150-5p and miR-145-5p, were down-regulated in the OIR rat retina compared to normoxic rats. Of these identified miRNAs, miR-143 is enriched in the retina and was first reported being associated with retinal neovascularization. Restoration of the down-regulated miRNAs by intravitreal delivery of miR-143, miR-126 or miR-150 mimics significantly suppressed retinal neovascularization in OIR rats. RNA-Seq revealed that miR-143 alleviated retinal neovascularization by regulating angiogenesis/inflammation pathways via fos signalling. Moreover, computational analysis indicated that a miRNA-143-targeted gene, transforming growth factor-beta activated kinase 1 (TAK1), is involved in several key pathways associated with retinal neovascularization and dysregulated miRNAs. Genetic and pharmacological inhibition of TAK1 suppressed retinal neovascularization and vascular inflammation in OIR rats.

Conclusions : Our data highlight the utility of next-generation sequencing for the development of therapeutics for retinal neovascularization and indicate that miR-143 plays a protective role against ischemia-induced retinal neovascularization.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.