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Digoxin inhibits retinal ischemia‐induced HIF‐1α expression and ocular neovascularization
Author(s) -
Yoshida Tsunehiko,
Zhang Huafeng,
Iwase Takeshi,
Shen Jikui,
Semenza Gregg L.,
Campochiaro Peter A.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-145664
Subject(s) - neovascularization , digoxin , retinal , retina , intraperitoneal injection , hypoxia (environmental) , medicine , pharmacology , in vivo , vascular endothelial growth factor , ischemia , vascular permeability , endocrinology , angiogenesis , chemistry , biology , ophthalmology , neuroscience , vegf receptors , heart failure , microbiology and biotechnology , organic chemistry , oxygen
Digoxin and other cardiac glycosides in‐hibit hypoxia‐inducible factor‐1 (HIF‐1) transcriptional activity in cultured cells and suppress tumor xenograft growth. We tested the hypothesis that digoxin reduces HIF‐1 levels in ischemic tissue in vivo and suppresses neovascularization. Well‐established murine models of ocular neovascularization were used to test our hypothesis. In mice with ischemic retinopathy, intraocular or intraperitoneal injection of digoxin markedly reduced retinal levels of HIF‐1α protein and mRNAs encoding multiple hypoxia‐regulated proangiogenic proteins and their receptors. Daily intraperitoneal injection of 2 mg/kg starting at postnatal day (P) 12 or a single intravitreous injection of 100 ng of digoxin at P12 reduced retinal neovascularization by >70% at P17. Digoxin also reduced the number of CXCR4 + cells and F4/80 + macrophages in ischemic retina and significantly reduced choroidal neovascularization at Bruch's membrane rupture sites. Digoxin suppresses retinal and choroidal neovascularization by reducing HIF‐1α levels, which blocks several proangiogenic pathways. Since digoxin suppresses multiple pathways in addition to VEGF signaling, it may provide advantages over specific VEGF antagonists for treatment of patients with retinal and choroidal diseases complicated by neovascularization and/or excessive vascular permeability. It may also be useful for treatment of neovascular diseases in other tissues.—Yoshida, T., Zhang, H., Iwase, T., Shen, J., Semenza, G. L., Campochiaro, P. A. Digoxin inhibits retinal ischemia‐induced HIF‐1α expression and ocular neovascularization. FASEB J. 24, 1759–1767 (2010). www.fasebj.org