Journal
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume 53, Issue 12, Pages 7718-7726Publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.11-8790
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Funding
- National Research Foundation (NRF)
- Korea government (MEST) [2012-0006019]
- Bio-Signal Analysis Technology Innovation Program of MEST/NRF, Republic of Korea [2012-0006058]
- Mid-Career Researcher Program of MEST/NRF, Republic of Korea [2012-0004931]
- Korea Institute of Oriental Medicine (KIOM) [K11040]
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PURPOSE. Oxidative stress-induced vascular endothelial growth factor (VEGF) is thought to play a critical role in the pathogenesis of retinopathy of prematurity (ROP). This study was performed to investigate the anti-angiogenic effect of luteolin against reactive oxygen species (ROS)-induced retinal neovascularization. METHODS. The toxicity of luteolin was evaluated through modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in human retinal microvascular endothelial cells (HRMECs) as well as TUNEL staining in the retina of C57BL/6J mice. After intravitreal injection of luteolin in the mouse model of ROP, retinal neovascularization was examined by fluorescence angiography and vessel counting. Anti-angiogenic activity of luteolin was evaluated by VEGF-induced migration and tube formation assay. The effect of luteolin on tertiary-butylhydroperoxide (t-BH)-induced ROS production was measured with 2070-dichlorofluorescein diacetate. The effect of luteolin on t-BH-induced and hypoxia-induced VEGF transcription and expression were evaluated by RT-PCR and Western blot, respectively. RESULTS. Luteolin never affected the viability of HRMECs up to 10 mu M, where luteolin never induced any structural change in all retinal layers. Luteolin inhibited retinal neovascularization in the mouse model of ROP. Moreover, VEGF-induced migration and tube formation were significantly decreased by cotreatment of luteolin. Luteolin attenuated VEGF transcription via blockade of t-BH-induced ROS production. Luteolin sup-pressed hypoxia-induced VEGF expression via attenuating hypoxia inducible factor 1 a expression. CONCLUSIONS. Our results suggest that luteolin could be a potent anti-angiogenic agent for retinal neovascularization, which is related to anti-oxidative activity to block ROS production and to subsequently suppress VEGF expression and the proangiogenic effect of VEGF. (Invest Ophthalmol Vis Sci. 2012;53:7718-7726) DOI:10.1167/iovs.11-8790
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