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R. Mohan, Y.-E. Kim, D. M. Markovitz, P. B. Mohan; The Anti-Angiogenic Activity of Withaferin A Is Mediated by the Intermediate Filament Protein Vimentin. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3202.
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The small molecule inhibitor withaferin A (WFA) is a potent inhibitor of new blood vessel growth (Mohan et al., Angiogenesis 2004) and exerts its biological activities by affecting sprouting angiogenesis (Bargagna-Mohan et al., IOVS 2006). We have exploited the chemical genetic approach (Yokota et al., Bioorg. Med. Chem. Lett. 2006) and identified that the binding target of WFA is the intermediate filament protein vimentin. The goal of this study was to validate vimentin is the in vivo target of this new class of angiogenesis inhibitor.
We employed the mouse model of corneal inflammatory angiogenesis in 129/Svev wild type and vimentin-deficient mice. Corneas were topically anesthetized and treated with dilute sodium hydroxide and corneal and limbal epithelium was gently removed by mechanical scraping. Mice were treated with vehicle or WFA (2 mg/kg/d) for a period of 10 days post-injury and corneal neovascularization was assessed by CD31 staining of corneal flat-mounts.
We show that wild-type and vimentin-deficient mice demonstrate injury-induced neovascularization of corneal tissues, although with vimentin-deficiency there are both qualitative and quantitative differences in capillary growth. When subjected to treatment with WFA, as anticipated, we observe dramatic inhibition of corneal vascularization in wild-type mice, but vimentin-deficient mice are significantly attenuated in their drug-induced inhibitory response.
In combination with our parallel cell culture findings that demonstrate WFA’s dominant-negative effects on vimentin intermediate filament structure and validation for the requirement of vimentin for WFA’s in vivo anti-angiogenic activity, we propose that WFA is both a versatile chemical genetic probe of vimentin function and a useful drug lead for pharmaceutical development.
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