Inhibition of hypoxia-induced retinal neovascularization in mice with short hairpin RNA targeting Rac1, possibly via blockading redox signaling

Xiong-Ze Zhang, Xi Huang, Ji-Hong Qiao, Jun-Jun Zhang, Mei-Xia Zhang
Experimental Eye Research 2011, 92 (6): 473-81
NADPH oxidase-derived reactive oxygen species are involved in angiogenesis in vitro and regulated by ras-related C3 botulinum toxin substrate 1 (Rac1). This study has employed vector-based short hairpin RNA targeting Rac1 (Rac1-shRNA) to investigate the inhibitory effect on hypoxia-induced retinal neovascularization (RN) in vivo and the underlying mechanism. pSUPER-Rac1-shRNA was intravitreally injected into the mouse model of oxygen-induced retinopathy. RN was evaluated by FITC-dextran angiography and quantitated histologically. Expressions of Rac1, nuclear factor kappa B (NF-κB) subunit p65, hypoxia-inducible factor-1 alpha (HIF-1α), and vascular endothelial growth factor (VEGF) were determined by real-time quantitative RT-PCR and western blotting. After intravitreal administration of pSUPER-Rac1-shRNA, retinal Rac1 gene expression was reduced by 72% at postnatal day 17 (P17). Retinal flat mount and quantification of the neovascular nuclei demonstrated that RN was significantly inhibited. Meanwhile, the expression levels of NF-κB and HIF-1α, the redox-dependent transcription factors, were significantly downregulated. HIF-1α and its downstream gene VEGF were found to be significantly decreased at both transcriptional and translational levels. Our findings not only suggest that Rac1 may be involved in the process of RN in mouse oxygen-induced retinopathy via regulating the redox signaling, but may also provide a novel therapeutic target for hypoxia-induced retinal neovascular diseases.

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