ArticleProceedings of the National Academy of Sciences of the United States of America2020
An allosteric peptide inhibitor of HIF-1α regulates hypoxia-induced retinal neovascularization.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 57 citations in OpenAlex.
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- Diabetic retinopathy and kidney involvement in adults with type 2 diabetes in high-altitude Tibet: A cross-sectional subanalysis of the China National Diabetic Chronic Complications Study.The Journal of international medical research · 2026Article
- Molecular stress and neurovascular injury in the diabetic retina.The Journal of clinical investigation · 2026Review
- Novel insights into β3-adrenoceptor function in a model of retinopathy of prematurity: the contribution of astrocytes to retinal protection.Frontiers in neuroscience · 2026Article
- Super-Enhancer Target Gene CBP/p300-Interacting Transactivator With Glu/Asp-Rich C-Terminal Domain, 2 Cooperates With Transcription Factor Forkhead Box J3 to Inhibit Pulmonary Vascular Remodeling.Cell proliferation · 2025Article
- P300 Promotes RUNX1 Transcription to Regulate Autophagy and Drive Corneal Neovascularization.Investigative ophthalmology & visual science · 2025Article
- Inhibition of Endothelial HIF-1α by IDF-11774 Attenuates Retinal Neovascularization and Vascular Leakage.Investigative ophthalmology & visual science · 2025Article
- Semaphorin 6A phase separation sustains a histone lactylation-dependent lactate buildup in pathological angiogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Novel Therapeutic Approaches for Treatment of Diabetic Retinopathy and Age-Related Macular Degeneration.Vision (Basel, Switzerland) · 2025Review
- The HAT Inhibitor ISOX-DUAL Diminishes Ischemic Areas in a Mouse Model of Oxygen-Induced Retinopathy.Genes to cells : devoted to molecular & cellular mechanisms · 2025Article
- Inhibition of Retinal Neovascularization by BEZ235: Targeting the Akt/4EBP1/Cyclin D1 Pathway in Endothelial Cells.Investigative ophthalmology & visual science · 2025Article
- Proliferative Diabetic Retinopathy Microenvironment Drives Microglial Polarization and Promotes Angiogenesis and Fibrosis via Cyclooxygenase-2/Prostaglandin E2 Signaling.International journal of molecular sciences · 2024Article
- Site-directed allostery perturbation to probe the negative regulation of hypoxia inducible factor-1α.RSC chemical biology · 2024Article
- The Role of HIF-1α in Retinopathy of Prematurity: A Review of Current Literature.Journal of clinical medicine · 2024Review
- Hypoxia and the endometrium: An indispensable role for HIF-1α as therapeutic strategies.Redox biology · 2024Review
- Linking Vascular Structure and Function: Image-Based Virtual Populations of the Retina.Investigative ophthalmology & visual science · 2024Article
- Targeting hypoxia-inducible factors: therapeutic opportunities and challenges.Nature reviews. Drug discovery · 2024Review
- Retinopathy of Prematurity-Targeting Hypoxic and Redox Signaling Pathways.Antioxidants (Basel, Switzerland) · 2024Review
- UCHL1 alleviates apoptosis in chondrocytes via upregulation of HIF‑1α‑mediated mitophagy.International journal of molecular medicine · 2023Article
- Enhanced therapeutic effect of PEDF-loaded mesenchymal stem cell-derived small extracellular vesicles against oxygen-induced retinopathy through increased stability and penetrability of PEDF.Journal of nanobiotechnology · 2023Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Retinal neovascularization (NV), a leading cause of vision loss, results from localized hypoxia that stabilizes the hypoxia-inducible transcription factors HIF-1α and HIF-2α, enabling the expression of angiogenic factors and genes required to maintain homeostasis under conditions of oxygen stress. HIF transcriptional activity depends on the interaction between its intrinsically disordered C-terminal domain and the transcriptional coactivators CBP/p300. Much effort is currently directed at disrupting protein-protein interactions between disease-associated transcription factors like HIF and their cellular partners. The intrinsically disordered protein CITED2, a direct product of HIF-mediated transcription, functions as a hypersensitive negative regulator that attenuates the hypoxic response by competing allosterically with HIF-1α for binding to CBP/p300. Here, we show that a peptide fragment of CITED2 is taken up by retinal cells and efficiently regulates pathological angiogenesis in murine models of ischemic retinopathy. Both vaso-obliteration (VO) and NV were significantly inhibited in an oxygen-induced retinopathy (OIR) model following intravitreal injection of the CITED2 peptide. The CITED2 peptide localized to retinal neurons and glia, resulting in decreased expression of HIF target genes. Aflibercept, a commonly used anti-VEGF therapy for retinal neovascular diseases, rescued NV but not VO in OIR. However, a combination of the CITED2 peptide and a reduced dose of aflibercept significantly decreased both NV and VO. In contrast to anti-VEGF agents, the CITED2 peptide can rescue hypoxia-induced retinal NV by modulating the hypoxic response through direct competition with HIF for CBP/p300, suggesting a dual targeting strategy for treatment of ischemic retinal diseases and other neovascular disorders.
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