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Marianne Berdugo, Charlotte Andrieu-Soler, Marc Doat, Yves Courtois, David BenEzra, Francine Behar-Cohen; Downregulation of IRS-1 Expression Causes Inhibition of Corneal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2005;46(11):4072-4078. doi: 10.1167/iovs.05-0105.
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purpose. The antiangiogenic effect of an antisense oligodeoxynucleotide (ODN) targeting insulin receptor substrate (IRS)-1 was evaluated on rat corneal neovascularization.
methods. Eyes with neovessels were treated with subconjunctival injections of IRS-1 antisense oligonucleotide (ASODN), IRS-1 sense ODN (SODN), or PBS. At 8 and 24 hours after the first subconjunctival injection, the expression of IRS-1, VEGF, and IL-1β mRNA was evaluated. IRS-1 protein levels were also measured at 8 hours by Western blot analysis (n = 4/group). On day 10, corneal neovascularization was quantified in flatmount corneas of rats treated daily from days 4 to 9.
results. On day 10, new vessels covered 95.5% ± 4% of the corneal area in PBS-treated eyes, 92% ± 7% in SODN-treated eyes and 59% ± 20% in ASODN-treated eyes (P < 0.001). In the ASODN-treated group, the expression and synthesis of IRS-1 were significantly downregulated when compared with the control groups. ASODN did not significantly affect the expression of VEGF but significantly decreased the expression of IL-1β at 24 hours (P = 0.04).
conclusions. Subconjunctival injections of IRS-1 antisense ODN significantly inhibit rat corneal neovascularization. This effect may be mediated by a downregulation of IL-1β. IRS-1 proteins may be interesting targets for the regulation of angiogenesis mediated by insulin, hypoxia, or inflammation.
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