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R. Mohan, R. Paranthan, P. Bargagna-Mohan; Withaferin A Induces p27Kip1 Expression to Inhibit Corneal Angio-Fibrosis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2037.
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The small molecule inhibitor withaferin A (WFA) is a potent inhibitor of corneal angiogenesis. Here we have investigated WFA’s activity in the alkali injury model of corneal angiofibrosis to unravel this inhibitor’s protective mechanism that reinstates corneal homeostasis.
We employed the alkali burn injury model (brief application of 0.15 N NaOH with removal of corneal epithelium) to induce corneal angiogenesis with fibrosis. Mice were treated by intraperiteoneal injection of WFA at 2 mg/kg daily for 7 or 14 days. Mouse eyes were cryosectioned and stained with anti-bodies against p27Kip1 and alpha-smooth muscle actin. Tissues from corneas were also subjected to western blotting. Mouse corneas were assessed after 7 and 14 days post injury and photographed to record the extent of corneal haze.
We show that upon injury the cornea is resurfaced with a defective epithelium that fails to express p27Kip1 by 7 days. These injured corneas also manifest abundant corneal blood vessels and fibrosis is revealed with loss of corneal clarity. Injured mice treated with 2 mg/kg WFA recover the full expression levels of p27Kip1 that is found in epithelial cell nuclei of uninjured controls. The induction of corneal epithelial recovery promoted by WFA was further extended in the stroma by downregulation of alpha-smooth muscle actin expression. The coordinated inhibition of corneal blood vessels and the recovery of corneal clarity became more prominent after 2 weeks of WFA treatment.
WFA coordinately affects the expression of p27Kip1, which is a critical cell cycle regulator in the epithelium, and downregulates stromal fibrotic responses to effectively block corneal angiogenesis and regain corneal homeostasis.
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