Digoxin inhibits retinal ischemia-induced HIF-1alpha expression and ocular neovascularization.
Digoxin and other cardiac glycosides inhibit 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-1alpha 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-1alpha 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
Tsunehiko
T
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Zhang
Huafeng
H
Iwase
Takeshi
T
Shen
Jikui
J
Semenza
Gregg L
GL
Campochiaro
Peter A
PA
D000818:Animals; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism; D004077:Digoxin / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
D002316:Cardiotonic Agents; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042442:Vascular Endothelial Growth Factors; D004077:Digoxin; D010100:Oxygen