Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression.
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.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
Monica
M
Guma
Jordi
J
Rius
Karen X
KX
Duong-Polk
Gabriel G
GG
Haddad
James D
JD
Lindsey
Michael
M
Karin
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012164:Retinal Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D048055:Mitogen-Activated Protein Kinase 8