SYVN1 Promotes STAT3 Protein Ubiquitination and Exerts Antiangiogenesis Effects in Retinopathy of Prematurity Development.

Abstract

Purpose:

SYVN1, a gene involved in endoplasmic reticulum-associated degradation, has been found to exert a protective effect by inhibiting inflammation in retinopathy. This study aimed to clarify whether SYVN1 is involved in the pathogenesis of retinopathy of prematurity (ROP) and its potential as a candidate for target therapy.

Methods:

Human retinal microvascular endothelial cells (hRMECs) and a mouse model of oxygen-induced retinopathy (OIR) were used to reveal the retinopathy development-associated protein expression and molecular mechanism. An adenovirus overexpressing SYVN1 or vehicle control was injected intravitreally at postnatal day 12 (P12), and the neovascular lesions were evaluated in retinal flatmounts with immunofluorescence staining, and hematoxylin and eosin staining at P17. Visual function was assessed by using electroretinogram (ERG).

Results:

Endogenous SYVN1 expression dramatically decreased in hRMECs under hypoxia and in ROP mouse retinas. SYVN1 regulated the signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor (VEGF) axis. SYVN1 overexpression promoted ubiquitination and degradation of STAT3, decreased the levels of phospho-STAT3, secretion of VEGF, and formation of neovascularization in hRMECs, which could be rescued by STAT3 activator treatment. In addition, SYVN1 overexpression prevented neovascularization and extended physiologic retinal vascular development in the retinal tissues of OIR mice without affecting retinal function.

Conclusions:

SYVN1 has a protective effect against OIR, and the molecular mechanisms are partly through SYVN1-mediated ubiquitination of STAT3 and the subsequent downregulation of VEGF. These findings strongly support our assumption that SYVN1 confers ROP resistance and may be a potentially novel pharmaceutical target against proliferative retinopathy.

• Authors: Shimei Chen, Jian Zhang, Dandan Sun, Yidong Wu, Junwei Fang, Xiaoling Wan, Shenping Li, Shuchang Zhang, Qing Gu, Qing Shao, Jun Dong, Xun Xu, Fang Wei, Qiao Sun
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 64 Issue 11 Pg. 8 (08 01 2023) ISSN: 1552-5783 [Electronic] United States
• PMID: 37540175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Vascular Endothelial Growth Factor A
• STAT3 Transcription Factor
• Oxygen
• SYVN1 protein, human
• Ubiquitin-Protein Ligases
• STAT3 protein, human

Topics

• Infant, Newborn
• Animals
• Mice
• Humans
• Retinopathy of Prematurity (pathology)
• Retinal Neovascularization (metabolism)
• Angiogenesis Inhibitors (therapeutic use)
• Vascular Endothelial Growth Factor A (metabolism)
• STAT3 Transcription Factor (metabolism)
• Endothelial Cells (metabolism)
• Endoplasmic Reticulum-Associated Degradation
• Oxygen (metabolism)
• Neovascularization, Pathologic (metabolism)
• Ubiquitination
• Disease Models, Animal
• Mice, Inbred C57BL
• Animals, Newborn
• Ubiquitin-Protein Ligases (genetics)