Digoxin inhibits development of hypoxic pulmonary hypertension in mice

作者：Abud Edsel M; Maylor Julie; Undem Clark; Punjabi Arjun; Zaiman Ari L; Myers Allen C; Sylvester J T; Semenza Gregg L^*; Shimoda Larissa A

来源：Proceedings of the National Academy of Sciences, 2012, 109(4): 1239-1244.

DOI：10.1073/pnas.1120385109

• acriflavine
• cardiac glycosides
• pulmonary circulation

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 ([Ca2+](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 [Ca2+](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 [Ca2+](i). These preclinical data support a role for HIF-1 inhibitors in the treatment of HPH.

• 出版日期2012-1-24