Digoxin inhibits development of hypoxic pulmonary hypertension in mice

Edsel M. Abud, Julie Maylor, Clark Undem, Arjun Punjabi, Ari L. Zaiman, Allen C. Myers, J. T. Sylvester, Gregg L. Semenza, Larissa A. Shimoda

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1239-1244
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number4
DOIs
StatePublished - Jan 24 2012

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Keywords

  • Acriflavine
  • Cardiac glycosides
  • Pulmonary circulation

ASJC Scopus subject areas

  • General

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