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J. Kim, J. Kim, Y. Yu, H.-J. Kwon, K.-W. Kim; Anti-Angiogenic Activity of N-hydroxy-7-(2-naphthylthio) Heptanomide in Retinal and Choroidal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1382.
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Histone deacetylase (HDAC), a key enzyme in gene expression, regulates angiogenic cytokine expression via HIF-1α pathway. Here, we report a new synthetic small molecule, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), as a HDAC inhibitor with anti-angiogenic activity to retinal and choroidal neovascularization both in vitro and in vivo.
The toxicity of HNHA was evaluated through MTT assay in human umbilical vein endothelial cells (HUVECs) as well as histological examination and TUNEL staining in the HNHA-injected retina. In addition, the effect of HNHA on physiologic retinal angiogenesis in development was assessed. Anti-angiogenic activity of HNHA was evaluated by in vitro tube formation assay and cell invasion assay of HUVECs. In C57BL/6 mice with OIR and laser-induced CNV, HNHA was injected intravitreously. Retinal and choroidal angiogenesis were examined by fluorescence angiography and vessel counting in cross sections.
The compound inhibited HDAC enzyme activity as well as proliferation of HUVECs in vitro. Treatment of cells with HNHA elicited histone hyperacetylation leading to an up-regulation of p21 transcription, cell cycle arrest, and an inhibition of tube formation and cell invasion of HUVECs. Moreover, HNHA significantly reduces VEGF expression via down-regulation of HIF-1α. HNHA effectively inhibited retinal and choroidal neovascularization with no reduction or retardation in retinal vascular development and no retinal toxicity.
Our data demonstrates that this novel HDAC inhibitor, HNHA, could be developed as a potential anti-angiogenic agent targeting HDAC to inhibit retinal and choroidal neovascularization.
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