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Cited by 80Retinopathy of Prematurity StudiesRetinal Diseases and TreatmentsAngiogenesis and VEGF in Cancer

Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression

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Guma, Monica, Rius, Jordi, Duong-Polk, Karen X., Haddad, Gabriel G., Lindsey, James D., Karin, Michael·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0902659106PMC PMC2688966
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Abstract

Many ocular pathologies, including retinopathy of prematurity (ROP), diabetic retinopathy, and age-related macular degeneration, result in vision loss because of aberrant neoangiogenesis. A common feature of these conditions is the presence of hypoxic areas and overexpression of the proangiogenic vascular endothelial growth factor (VEGF). The prevailing current treatment, laser ablation of the retina, is destructive and only partially effective. Preventive and less destructive therapies are much more desirable. Here, we show that mice lacking c-Jun N-terminal kinase 1 (JNK1) exhibit reduced pathological angiogenesis and lower levels of retinal VEGF production in a murine model of ROP. We found that hypoxia induces JNK activation and regulates VEGF expression by enhancing the binding of phospho-c-Jun to the VEGF promoter. Intravitreal injection of a specific JNK inhibitor decreases retinal VEGF expression and reduces pathological retinal neovascularization without obvious side effects. These results strongly suggest that JNK1 plays a key role in retinal neoangiogenesis and that it represents a new pharmacological target for treatment of diseases where excessive neoangiogenesis is the underlying pathology.

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  • Activation of MAPK components-ERK, JNK, and p38 MAPK-has been observed in human RPE cultures and animal models of AMD.

    “Notably, activation of MAPK components-such as extracellular signal-regulated kinase (ERK), cJun N-terminal kinase (JNK), and p38 MAPK-has been observed in human RPE cultures and animal models of AMD 18,19”

    From rAAV-mediated Multi-miRNA Delivery Targeting MAPK Pathway Suppresses Laser-induced Choroidal Neovascularization in Mice (2026) · cites this paper as [19]

    The Results (page unavailable) report hypoxia-induced JNK activation in cells and increased c-Jun phosphorylation in retinas of mice with oxygen-induced retinopathy. They do not establish activation of ERK or p38 MAPK, or report these observations in human RPE cultures or animal models of AMD; the mouse model is described as a model of retinopathy of prematurity. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Guma, M., Rius, J., Duong-Polk, K. X., Haddad, G. G., Lindsey, J. D., & Karin, M.
Affiliations
  • Laboratory of Gene Regulation and Signal Transduction,
  • Hamilton Glaucoma Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723
  • Pediatrics, School of Medicine, and
  • University of California San Diego (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-05-26
Volume
106
Issue
21
Pages
8760-8765
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0902659106
PMC
PMC2688966
OpenAlex
W1981104972
Cited by
80
References
8
Citations by year
2026: 4 · 2025: 6 · 2024: 5 · 2023: 4 · 2021: 1 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 5 · 2014: 2 · 2013: 8 · 2012: 7
FWCI
7.05
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Environmental Health Sciences (R01ES006376)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinopathy of Prematurity Studies
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
JNK1, c-Jun N-terminal kinase, retinopathy of prematurity, hypoxia, VEGF expression, retinal neovascularization, pathological angiogenesis, c-Jun phosphorylation, VEGF promoter, JNK inhibitor, intravitreal injection, age-related macular degeneration, diabetic retinopathy
MeSH terms
Animals, Hypoxia, Cell Line, Disease Models, Animal, Enzyme Activation, Gene Expression Regulation, Neovascularization, Pathologic, Retinal Diseases, Transcription, Genetic, Vascular Endothelial Growth Factor A, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 8, Mice, Hypoxia-Inducible Factor 1, alpha Subunit

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