Halofuginone, a promising drug for treatment of pulmonary hypertension

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).

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.

Halofuginone increased voltage-gated K⁺ (K_v ) 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.

Halofuginone is a potent pulmonary vasodilator by activating K_v 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.