Document Detail


Digoxin inhibits development of hypoxic pulmonary hypertension in mice.
MedLine Citation:
PMID:  22232678     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic hypoxia is an inciting factor for the development of pulmonary arterial hypertension. The mechanisms involved in the development of hypoxic pulmonary hypertension (HPH) include hypoxia-inducible factor 1 (HIF-1)-dependent transactivation of genes controlling pulmonary arterial smooth muscle cell (PASMC) intracellular calcium concentration ([Ca(2+)](i)) and pH. Recently, digoxin was shown to inhibit HIF-1 transcriptional activity. In this study, we tested the hypothesis that digoxin could prevent and reverse the development of HPH. Mice were injected daily with saline or digoxin and exposed to room air or ambient hypoxia for 3 wk. Treatment with digoxin attenuated the development of right ventricle (RV) hypertrophy and prevented the pulmonary vascular remodeling and increases in PASMC [Ca(2+)](i), pH, and RV pressure that occur in mice exposed to chronic hypoxia. When started after pulmonary hypertension was established, digoxin attenuated the hypoxia-induced increases in RV pressure and PASMC pH and [Ca(2+)](i). These preclinical data support a role for HIF-1 inhibitors in the treatment of HPH.
Authors:
Edsel M Abud; Julie Maylor; Clark Undem; Arjun Punjabi; Ari L Zaiman; Allen C Myers; J T Sylvester; Gregg L Semenza; Larissa A Shimoda
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2012-01-09
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-02-06     Completed Date:  2012-03-28     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1239-44     Citation Subset:  IM    
Affiliation:
Division of Pulmonary and Critical Care Medicine, Vascular Program, Institute of Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Animals
Anoxia / complications*
Blood Pressure / drug effects
Calcium / metabolism
Digoxin / blood,  pharmacology*
Hypertension, Pulmonary / etiology,  prevention & control*
Hypertrophy, Right Ventricular / prevention & control
Hypoxia-Inducible Factor 1 / antagonists & inhibitors,  metabolism*
Mice
Microscopy, Confocal
Myocytes, Smooth Muscle / metabolism
Pulmonary Artery / cytology
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Transcriptional Activation / drug effects,  physiology*
Grant Support
ID/Acronym/Agency:
GM08074/GM/NIGMS NIH HHS; HL67191/HL/NHLBI NIH HHS; HL75389/HL/NHLBI NIH HHS; HL84762/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Hypoxia-Inducible Factor 1; 20830-75-5/Digoxin; 7440-70-2/Calcium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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