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Carli Wittgrove, Peter Westenskow, Toshihide Kurihara, Edith Aguilar, Stacey Moreno, Martin Friedlander; microRNA-30a Antagonism Inhibits Ras Signaling and Prevents Neovascularization. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4602.
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Cytokines including VEGF activate Ras, and Ras can be inactivated by RasGAP. microRNAs (miRNAs) regulate gene expression by promiscuously binding to the UTR of multiple mRNA transcripts. We are interested in identifying miRNAs that negatively regulate RasGAP to inhibit angiogenesis downstream of VEGF. We have previously reported that anti-miR-132 oligos potentiate RasGAP and prevent neovascularization. We have observed that miR-30a also regulates RasGAP in endothelial cells. Additionally, miR-30a reportedly regulates other angiogenesis-associated pathways and supporting cells. If anti-miR-30a can prevent pathological angiogenesis by targeting pathways distinct from anti-miR-132, additive or synergistic effects may be obtained by using them in combination.
RT-PCR, in-situ hybridization, and immunohistochemistry were performed to determine the endogenous expression pattern of miR-30a and RasGAP during development and in two murine ocular neovascular disease models, oxygen-induced retinopathy (OIR) and very low density lipoprotein receptor (VLDLR-/-) mutants. Anti-miR-30a was injected intravitreally in the disease models to determine if RasGAP could be modulated and neovascularization prevented. Gene profiling experiments were performed to identify target genes regulated by miR-30a and miR-132.
miR-30a and RasGAP have inverse expression patterns during critical times in ocular vascular development and both are dysregulated in the disease models examined. Anti-miR-30a injections result in upregulation of RasGAP preventing neovascularization as potently as anti-miR-132.
Anti-miR-30a and -132 significantly limit neovascularization in murine models of pathological ocular neovascularization. We suggest they do so largely by regulating RasGAP, although both regulate other genes as well. From analysis of these other targets we will determine if one antagomir is superior or safer than the other, or if combination therapies may provide the most pronounced effects and relief for patients with blinding neovascular diseases.
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