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

  • Life Sci. 2022 Mar 15:293:120089. doi: 10.1016/j.lfs.2021.120089.
Qingqiu Chen  1 ,  Li Tang  2 ,  Yi Zhang  3 ,  Chengyu Wan  1 ,  Xiuxian Yu  1 ,  Yuman Dong  1 ,  Xiaoting Chen  4 ,  Xueling Wang  5 ,  Ning Li  5 ,  Guang Xin  1 ,  Meixia Zhang  6 ,  Zhen Chen  1 ,  Hai Niu  1 ,  Wen Huang  7
Affiliations
  • 1. Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2. Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 3. Research Core Facility of West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 4. Animal Experimental Center of West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 5. Integrated Chinese and Western Medicine Department, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 6. Macular Disease Research Laboratory, Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 7. Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: [email protected].
PMID: 35007563 DOI: 10.1016/j.lfs.2021.120089
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.

Keywords
Autophagic flux; Retinal pigment epithelium; STING; Senescence; VEGF.
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