PMID- 20065104
OWN - NLM
STAT- MEDLINE
DCOM- 20100721
LR  - 20211020
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 24
IP  - 6
DP  - 2010 Jun
TI  - Digoxin inhibits retinal ischemia-induced HIF-1alpha expression and ocular 
      neovascularization.
PG  - 1759-67
LID - 10.1096/fj.09-145664 [doi]
AB  - 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.
FAU - Yoshida, Tsunehiko
AU  - Yoshida T
AD  - Department of Ophthalmology, Johns Hopkins University School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Zhang, Huafeng
AU  - Zhang H
FAU - Iwase, Takeshi
AU  - Iwase T
FAU - Shen, Jikui
AU  - Shen J
FAU - Semenza, Gregg L
AU  - Semenza GL
FAU - Campochiaro, Peter A
AU  - Campochiaro PA
LA  - eng
GR  - R01 EY012609/EY/NEI NIH HHS/United States
GR  - EY012609/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100111
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Cardiotonic Agents)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Messenger)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 73K4184T59 (Digoxin)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cardiotonic Agents/*pharmacology
MH  - Choroidal Neovascularization/*drug therapy/metabolism
MH  - Digoxin/*pharmacology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Oxygen/metabolism
MH  - RNA, Messenger/metabolism
MH  - Reperfusion Injury/*drug therapy/metabolism
MH  - Retinal Neovascularization/*drug therapy/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Vascular Endothelial Growth Factors/metabolism
PMC - PMC2874483
EDAT- 2010/01/13 06:00
MHDA- 2010/07/22 06:00
PMCR- 2011/06/01
CRDT- 2010/01/13 06:00
PHST- 2010/01/13 06:00 [entrez]
PHST- 2010/01/13 06:00 [pubmed]
PHST- 2010/07/22 06:00 [medline]
PHST- 2011/06/01 00:00 [pmc-release]
AID - fj.09-145664 [pii]
AID - 09-145664 [pii]
AID - 10.1096/fj.09-145664 [doi]
PST - ppublish
SO  - FASEB J. 2010 Jun;24(6):1759-67. doi: 10.1096/fj.09-145664. Epub 2010 Jan 11.