Downregulation of IRS-1 expression causes inhibition of corneal angiogenesis.

Abstract

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-1beta 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-1beta 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-1beta. IRS-1 proteins may be interesting targets for the regulation of angiogenesis mediated by insulin, hypoxia, or inflammation.

• Authors: Marianne Berdugo, Charlotte Andrieu-Soler, Marc Doat, Yves Courtois, David BenEzra, Francine Behar-Cohen
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 46 Issue 11 Pg. 4072-8 (Nov 2005) ISSN: 0146-0404 [Print] United States
• PMID: 16249482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Insulin Receptor Substrate Proteins
• Interleukin-1
• Irs1 protein, rat
• Oligodeoxyribonucleotides, Antisense
• Phosphoproteins
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, rat

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Blotting, Western
• Conjunctiva (drug effects)
• Corneal Neovascularization (metabolism, pathology, prevention & control)
• Disease Models, Animal
• Down-Regulation
• Immunohistochemistry
• Injections
• Insulin Receptor Substrate Proteins
• Interleukin-1 (genetics, metabolism)
• Oligodeoxyribonucleotides, Antisense (therapeutic use)
• Phosphoproteins (genetics, metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Inbred Lew
• Specific Pathogen-Free Organisms
• Vascular Endothelial Growth Factor A (genetics, metabolism)