The aim of this study is to investigate the specific molecular mechanism of high myopia (HM) is correlated with a lower risk of diabetic retinopathy (DR).

A total of 18 patients who visited the Department of Ophthalmology, Yangpu Hospital Affiliated to Tongji University from March to October 2019 were enrolled as study subjects, including 10 males and 8 females with a mean age of (70.1±4.3) years (ranging from 64 to 77 years). Blood samples were collected from 6 patients with HM, 6 patients with proliferative diabetic retinopathy (PDR), and 6 control subjects. Extracellular vesicles were isolated and characterized, then proteomic analysis was performed using liquid chromatography-tandem mass spectrometry with label-free quantification. Bioinformatics methods, including Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, were applied to analyze the functions of the differentially expressed proteins. Additionally, a form-deprivation myopia mouse model and a DR mouse model were established, and key proteins were validated by Western blot.

A total of 852 proteins of extracellular vesicles were identified in the proteomic data. Compared with control subjects, 16 specific proteins were identified in plasma extracellular vesicle specimens from HM patients and 6 specific proteins from PDR patients, with 700 common proteins. A total of 25 differentially expressed proteins were found. Compared with control subjects, HM patients had 75 differentially expressed proteins, including 20 up-regulated proteins and 55 down-regulated proteins. These proteins were mainly enriched in immune response and extracellular matrix-related pathways. Among them, the key protein E3 ubiquitin-protein ligase Itchy homolog (ITCH) was up-regulated in the HM group and down-regulated in the PDR group. The protein-protein interaction network of differential proteins in HM patients compared with control subjects contained 46 nodes and 320 edges. The differential proteins in HM patients compared with PDR patients contained 69 nodes and 676 edges in the protein-protein interaction network. A consistent expression trend occurred in scleral tissues of animal models.

HM may potentially inhibit the occurrence and progression of DR, and ITCH is likely involved in this process by regulating inflammatory pathways and retinal angiogenesis. The differential expression of ITCH in the two diseases and its underlying mechanistic pathways provide a new perspective for explaining the clinical observation that diabetic patients with HM tend to have milder DR and a lower risk of its progression.