Digoxin inhibits development of hypoxic pulmonary hypertension in mice.
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.
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.
Edsel M
EM
Abud
Julie
J
Maylor
Clark
C
Undem
Arjun
A
Punjabi
Ari L
AL
Zaiman
Allen C
AC
Myers
J T
JT
Sylvester
Gregg L
GL
Semenza
Larissa A
LA
Shimoda
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004077:Digoxin / Q000097:blood / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications*; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
D051793:Hypoxia-Inducible Factor 1; D004077:Digoxin; D002118:Calcium