title: Attenuation of choroidal neovascularization by histone deacetylase inhibitor.
abstract: Choroidal neovascularization (CNV) is a blinding complication of age-related macular degeneration that manifests as the growth of immature choroidal blood vessels through Bruch's membrane, where they can leak fluid or hemorrhage under the retina. Here, we demonstrate that the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) can down-regulate the pro-angiogenic hypoxia-inducible factor-1α and vascular endothelial growth factor (VEGF), and up-regulate the anti-angiogenic and neuro-protective pigment epithelium derived factor in human retinal pigment epithelial (RPE) cells. Most strikingly, TSA markedly down-regulates the expression of VEGF receptor-2 in human vascular endothelial cells and, thus, can knock down pro-angiogenic cell signaling. Additionally, TSA suppresses CNV-associated wound healing response and RPE epithelial-mesenchymal transdifferentiation. In the laser-induced model of CNV using C57Bl/6 mice, systemic administration of TSA significantly reduces fluorescein leakage and the size of CNV lesions at post-laser days 7 and 14 as well as the immunohistochemical expression of VEGF, VEGFR2, and smooth muscle actin in CNV lesions at post-laser day 7. This report suggests that TSA, and possibly HDACi's in general, should be further evaluated for their therapeutic potential for the treatment of CNV.
authors: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America; Doheny Eye Institute, Los Angeles, CA, United States of America.
authors: Nymph
authors: N
authors: Chan
authors: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America; Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America.
authors: Shikun
authors: S
authors: He
authors: Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America.
authors: Christine K
authors: CK
authors: Spee
authors: Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America.
authors: Keijiro
authors: K
authors: Ishikawa
authors: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America; Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States of America.
authors: David R
authors: DR
authors: Hinton
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000188:drug therapy / Q000209:etiology* / Q000662:veterinary; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005136:Eye Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use / Q000633:toxicity*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015843:Serpins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009414:Nerve Growth Factors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099174:Pigment Epithelium-Derived Factor; C497442:HIF1A protein, human; C012589:trichostatin A