STING up-regulates VEGF expression in oxidative stress-induced senescence of retinal pigment epithelium via NF-κB/HIF-1α pathway.

Abstract

AIM:

Aging-related dysfunction of retinal pigment epithelium (RPE) is the main pathogenic factors for pathological angiogenesis due to dysregulated vascular endothelial growth factor (VEGF) in retinal vascular diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). However, the molecular mechanism behind the up-regulation of VEGF in senescent RPE is still blurred.

MATERIALS AND METHODS:

As oxidative damage is the key cause of RPE dysfunction, we employed a model of oxidative stress-induced premature senescence of ARPE-19 to explore the effect of senescent RPE on VEGF.

KEY FINDINGS:

We reported that senescent ARPE-19 up-regulated VEGF expression under both short-term and prolonged H2O2 treatment, accompanying with increased HIF-1α, the key mediator of VEGF. STING signaling, which could be activated by oxidative stress-damaged DNA, was also observed to be increased in senescent ARPE-19 treated with H2O2. And the inhibition of STING significantly reduced HIF-1α expression to alleviate the up-regulation of VEGF. NF-κB was also shown to be involved in the regulation of VEGF in senescent ARPE-19 in response to STING signaling. Furthermore, oxidative stress impaired the lysosomal clearance of damaged DNA to enhance STING signaling, thereby up-regulating VEGF expression in senescent RPE.

SIGNIFICANCE:

Our data provide evidence that STING plays an important role in VEGF regulation in senescent RPE induced by oxidative stress.

• Authors: Qingqiu Chen, Li Tang, Yi Zhang, Chengyu Wan, Xiuxian Yu, Yuman Dong, Xiaoting Chen, Xueling Wang, Ning Li, Guang Xin, Meixia Zhang, Zhen Chen, Hai Niu, Wen Huang
• Journal: Life sciences (Life Sci) Vol. 293 Pg. 120089 (Mar 15 2022) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 35007563 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Membrane Proteins
• NF-kappa B
• STING1 protein, human
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Hydrogen Peroxide

Topics

• Cellular Senescence (drug effects, physiology)
• Gene Expression
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism, pathology)
• Humans
• Hydrogen Peroxide (toxicity)
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis)
• Macular Degeneration (metabolism, pathology)
• Membrane Proteins (biosynthesis)
• NF-kappa B (biosynthesis)
• Oxidative Stress (drug effects, physiology)
• Retinal Pigment Epithelium (drug effects, metabolism, pathology)
• Up-Regulation (drug effects, physiology)
• Vascular Endothelial Growth Factor A (biosynthesis)