Abstract
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 TGFbeta 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.
Highlights
The angiogenic process involves a complex series of cellular events including microvascular sprouting, endothelial proliferation, migration and tubule formation
JUN small interfering RNA (siRNA) can serve as a specific inhibitor of aberrant endothelial and neovascular growth
We evaluated the capacity of novel siRNA molecules targeting Jun mRNA to serve as inhibitors of JUN and JUN-dependent gene expression, microvascular endothelial cell proliferation, migration, tubule formation and retinal neovascularisation
Summary
The angiogenic process involves a complex series of cellular events including microvascular sprouting, endothelial proliferation, migration and tubule formation. It is known that some of these events are controlled at the level of transcription by nuclear regulatory factors such as Ets-1 (Iwasaka et al, 1996), hypoxia-inducible factor-1 (Boudreau et al, 1997), FOS (Marconcini et al, 1999) and early growth response-1 (Fahmy et al, 2003), more work is needed to provide greater understanding of the transcription factors involved. This information would help facilitate the design of factor-specific, anti-angiogenic strategies. JUN might be one of the factors influenced by endostatin in its inhibition of angiogenesis (Abdollahi et al, 2004)
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