Abstract
Purpose: :
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.
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Keywords: retinal neovascularization • choroid: neovascularization • neovascularization