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First published online 17 July 2006
doi: 10.1242/jcs.03059

Journal of Cell Science 119, 3219-3226 (2006)
Published by The Company of Biologists 2006
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Research Article

JUN siRNA regulates matrix metalloproteinase-2 expression, microvascular endothelial growth and retinal neovascularisation

Guishui Zhang1, Roger G. Fahmy1, Nick diGirolamo2 and Levon M. Khachigian1,*

1 Centre for Vascular Research, The University of New South Wales and Department of Haematology, The Prince of Wales Hospital
2 Inflammatory Diseases Research Unit, University of New South Wales, Sydney NSW 2052, Australia

* Author for correspondence (e-mail: L.Khachigian{at}unsw.edu.au)

Accepted 18 May 2006

Transcription factors link changes in the extracellular environment with alterations in gene expression. As such, these molecules serve as attractive targets for intervention in pathological settings. Since JUN has been linked with microvascular disease in humans, we hypothesised that small interfering RNA (siRNA) targeting this immediate-early gene may be useful agents that suppress endothelial growth and neovascularisation. Here we show that Jun siRNA inhibits Jun mRNA and protein expression in murine microvascular endothelial cells, blocks cell proliferation and suppresses migration in a scratch-wound assay. It also inhibits three-dimensional tubular formation on basement membrane extracts and reduces angiogenesis in mice bearing Matrigel plugs as subcutaneous implants. Single intravitreal administration of Jun siRNA reduces neovascularisation in a murine model of proliferative retinopathy, and suppresses endothelial JUN and matrix metalloproteinase-2 (MMP-2) immunoreactivity in retinal vessels, data supported by its repression of MMP-2 expression and gelatinolytic activity in vitro. Co-administration of TGFß with the siRNA reverses this neovascular inhibitory effect, which is in turn abrogated by cis-9-octadecenoyl-N-hydroxylamide, consistent with the involvement of a metalloproteinase such as MMP-2. Thus, JUN siRNA can serve as a specific inhibitor of aberrant endothelial and neovascular growth.

Key words: JUN, siRNA, Gene targeting, Endothelial cells, Retinal neovascularisation




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