Halofuginone, a promising drug for treatment of pulmonary hypertension

Pritesh P. Jain, Tengteng Zhao, Mingmei Xiong, Shanshan Song, Ning Lai, Qiuyu Zheng, Jiyuan Chen, Shane G. Carr, Aleksandra Babicheva, Amin Izadi, Marisela Rodriguez, Shamin Rahimi, Francesca Balistrieri, Shayan Rahimi, Tatum Simonson, Daniela Valdez-Jasso, Patricia A. Thistlethwaite, John Y.J. Shyy, Jian Wang, Ayako MakinoJason X.J. Yuan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background and Purpose: Halofuginone is a febrifugine derivative originally isolated from Chinese traditional herb Chang Shan that exhibits anti-hypertrophic, anti-fibrotic and anti-proliferative effects. We sought to investigate whether halofuginone induced pulmonary vasodilation and attenuates chronic hypoxia-induced pulmonary hypertension (HPH). Experimental Approach: Patch-clamp experiments were conducted to examine the activity of voltage-dependent Ca2+ channels (VDCCs) in pulmonary artery smooth muscle cells (PASMCs). Digital fluorescence microscopy was used to measure intracellular Ca2+ concentration in PASMCs. Isolated perfused and ventilated mouse lungs were used to measure pulmonary artery pressure (PAP). Mice exposed to hypoxia (10% O2) for 4 weeks were used as model of HPH for in vivo experiments. Key Results: Halofuginone increased voltage-gated K+ (Kv) currents in PASMCs and K+ currents through KCNA5 channels in HEK cells transfected with KCNA5 gene. HF (0.03–1 μM) inhibited receptor-operated Ca2+ entry in HEK cells transfected with calcium-sensing receptor gene and attenuated store-operated Ca2+ entry in PASMCs. Acute (3–5 min) intrapulmonary application of halofuginone significantly and reversibly inhibited alveolar hypoxia-induced pulmonary vasoconstriction dose-dependently (0.1–10 μM). Intraperitoneal administration of halofuginone (0.3 mg·kg−1, for 2 weeks) partly reversed established PH in mice. Conclusion and Implications: Halofuginone is a potent pulmonary vasodilator by activating Kv channels and blocking VDCC and receptor-operated and store-operated Ca2+ channels in PASMCs. The therapeutic effect of halofuginone on experimental PH is probably due to combination of its vasodilator effects, via inhibition of excitation–contraction coupling and anti-proliferative effects, via inhibition of the PI3K/Akt/mTOR signalling pathway.

Original languageEnglish (US)
Pages (from-to)3373-3394
Number of pages22
JournalBritish Journal of Pharmacology
Volume178
Issue number17
DOIs
StatePublished - Sep 2021
Externally publishedYes

Keywords

  • Ca channel
  • K channel
  • KCNA5
  • Pulmonary arterial hypertension
  • halofuginone
  • smooth muscle cell
  • treatment

ASJC Scopus subject areas

  • Pharmacology

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