Aflibercept Intervention in Experimental Branch Retinal Vein Occlusion Results in Upregulation of DnaJ Homolog Subfamily C Member 17.

Lasse Jørgensen Cehofski,Alexander Nørgård Alsing,Jonas Ellegaard Nielsen,Svend Kirkeby,Anders Kruse,Benn Falch Sejergaard,Danson Vasanthan Muttuvelu,Henrik Vorum,Bent Honoré,Shona Pedersen,Alessandro Meduri

doi:10.1155/2021/6690260

Abstract

Aflibercept is an inhibitor of vascular endothelial growth factor (VEGF) used to treat macular edema following branch retinal vein occlusion (BRVO). Despite well-documented efficacy, there is limited knowledge about proteome changes following aflibercept intervention in BRVO. Proteome changes may provide insights into mechanisms of action as well as aspects related to safety profile. In seven Danish Landrace pigs, BRVO was induced with a well-established experimental model of argon laser-induced BRVO. BRVO was induced in both eyes. Three days after the induced BRVO, aflibercept was injected intravitreally in the right eyes, while the left eyes received intravitreal isotonic saline water. Retinas were collected 15 days after the induced BRVO and analyzed with label-free quantification liquid chromatography tandem mass spectrometry (LFQ LC-MS/MS). Fourteen proteins were changed in expression following aflibercept intervention in the BRVO model. LFQ LC-MS/MS identified an upregulation of DnaJ homolog subfamily C member 17 (DNAJC17) (fold change = 6.19) and a modest downregulation of isoform 2 of the protein encoded by N-myc downstream regulated gene 2 (NDRG2) (fold change = 0.40). NDRG2 was unchanged by Western blotting. In the additional significantly regulated proteins, only discrete changes were observed (fold changes 0.52–1.59). Our study is the first to report an association between aflibercept intervention and the heat shock protein DNAJC17. Our results indicate that the role of heat shock proteins in the treatment of BRVO should be further explored.

Highlights

Branch retinal vein occlusion (BRVO) is the most frequent retinal vascular disease after diabetic retinopathy [1]
We aimed at identifying large-scale retinal protein changes following aflibercept intervention in experimental BRVO
Our study identified an upregulation of the heat shock protein DnaJ homolog subfamily C member 17 (DNAJC17) following aflibercept intervention in experimental BRVO

Summary

Introduction

Branch retinal vein occlusion (BRVO) is the most frequent retinal vascular disease after diabetic retinopathy [1]. Occlusion of a retinal branch vein is known to cause retinal non-perfusion, retinal ischemia, and hypoxia, resulting in the release of vascular endothelial growth factor (VEGF). Increased VEGF levels result in breakdown of the blood-retinal barrier leading to increased vascular permeability and formation of macular edema [1, 2, 4, 5]. Macular edema is a vision-limiting complication to BRVO which is effectively treated with intravitreal injections of VEGF inhibitors including bevacizumab, ranibizumab, and aflibercept [4, 6,7,8,9]. Bevacizumab and ranibizumab bind and neutralize all isoforms of VEGF-A [10]. Aflibercept binds all isoforms of VEGF-A, VEGF-B, and placental growth factor [2, 11]. Using immunoprecipitation with aflibercept and retinal pigment epithelium (RPE) cell extracts, Kanda et al [12] found that aflibercept binds galectin-1 and suppresses galectin-1 mediated activation of VEGFR-2

Results

Discussion

Conclusion