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Rania S. Sulaiman, Myunghoe Heo, Sanha Lee, Seung-Yong Seo, Timothy William Corson; Soluble Epoxide Hydrolase Is a Therapeutic Target for Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1957.
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© ARVO (1962-2015); The Authors (2016-present)
Sight-threatening choroidal neovascularization (CNV) is key to the pathophysiology of wet age-related macular degeneration (AMD). Current therapies target vascular endothelial growth factor signaling, but are associated with some limitations. Therefore, the characterization of alternative angiogenic pathways is crucial to understand the disease pathology and provide novel drug targets. We previously identified the bioactive lipid metabolizing enzyme soluble epoxide hydrolase (sEH) as a target of an antiangiogenic small molecule that we developed. Here, we further characterized sEH expression in mouse and human eyes and evaluated the effect of a known sEH inhibitor on CNV ex vivo and in vivo in the L-CNV mouse model.
sEH expression in mouse eyes with L-CNV and human eyes with wet AMD was evaluated by immunofluorescence and compared to age-matched controls. The choroidal sprouting assay evaluated the effects of sEH inhibitor “7t” (7-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)benzo[d]isoxazol-3-amine) on choroidal endothelium ex vivo. Eight week old mice received choroidal laser burns and an intravitreal injection of vehicle, 7t, or anti-VEGF164. After 14 days, eyes were enucleated and CNV lesion volumes were calculated from Z-stack confocal images of agglutinin-stained choroids.
Immunofluorescence staining revealed a substantial upregulation of retinal sEH in mouse L-CNV and human wet AMD eyes compared to controls. In mice, sEH was not upregulated in Müller cells, cone photoreceptors, or retinal ganglion cells as indicated by lack of sEH co-staining with vimentin, arrestin and Brn3a antibodies. Interestingly, sEH overexpression was evident in rod photoreceptors as indicated by sEH/rhodopsin co-staining. sEH inhibitor 7t significantly suppressed choroidal sprouting ex vivo at 10 µM concentration, P<0.01. Additionally, 10 µM 7t caused about 35% suppression of neovascular lesion volume, compared to vehicle-treated control, in vivo in the L-CNV mouse model, P<0.01.
These data demonstrate that sEH is an important angiogenic mediator in CNV. Small molecule inhibitors of sEH could be an exciting approach alone or in combination with the standard anti-VEGF therapies for the treatment of ocular neovascular diseases such as wet AMD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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