JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration.

Abstract

Age-related macular degeneration (AMD) is the leading cause of registered blindness among the elderly and affects over 30 million people worldwide. It is well established that oxidative stress, inflammation, and apoptosis play critical roles in pathogenesis of AMD. In advanced wet AMD, although, most of the severe vision loss is due to bleeding and exudation of choroidal neovascularization (CNV), and it is well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels. VEGF suppression therapy improves visual acuity in AMD patients. However, there are unresolved issues, including safety and cost. Here we show that mice lacking c-Jun N-terminal kinase 1 (JNK1) exhibit decreased inflammation, reduced CNV, lower levels of choroidal VEGF, and impaired choroidal macrophage recruitment in a murine model of wet AMD (laser-induced CNV). Interestingly, we also detected a substantial reduction in choroidal apoptosis of JNK1-deficient mice. Intravitreal injection of a pan-caspase inhibitor reduced neovascularization in the laser-induced CNV model, suggesting that apoptosis plays a role in laser-induced pathological angiogenesis. Intravitreal injection of a specific JNK inhibitor decreased choroidal VEGF expression and reduced pathological CNV. These results suggest that JNK1 plays a key role in linking oxidative stress, inflammation, macrophage recruitment apoptosis, and VEGF production in wet AMD and pharmacological JNK inhibition offers a unique and alternative avenue for prevention and treatment of AMD.

• Authors: Hongjun Du, Xufang Sun, Monica Guma, Jing Luo, Hong Ouyang, Xiaohui Zhang, Jing Zeng, John Quach, Duy H Nguyen, Peter X Shaw, Michael Karin, Kang Zhang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 6 Pg. 2377-82 (Feb 05 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23341606 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amino Acid Chloromethyl Ketones
• Cysteine Proteinase Inhibitors
• Cytokines
• Inflammation Mediators
• Vascular Endothelial Growth Factor A
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• vascular endothelial growth factor A, mouse
• Mitogen-Activated Protein Kinase 8

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Apoptosis (drug effects, physiology)
• Choroidal Neovascularization (drug therapy, metabolism, pathology, prevention & control)
• Cysteine Proteinase Inhibitors (pharmacology)
• Cytokines (metabolism)
• Disease Models, Animal
• Humans
• Inflammation Mediators (metabolism)
• Macrophages (pathology)
• Macular Degeneration (drug therapy, metabolism, pathology, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 8 (antagonists & inhibitors, deficiency, genetics)
• Oxidative Stress
• Vascular Endothelial Growth Factor A (biosynthesis)