Halofuginone, a promising drug for treatment of pulmonary hypertension

  • Br J Pharmacol. 2021 Sep;178(17):3373-3394. doi: 10.1111/bph.15442.
Pritesh P Jain  1 ,  Tengteng Zhao  1 ,  Mingmei Xiong  1  2 ,  Shanshan Song ,  Ning Lai  1  3 ,  Qiuyu Zheng  4 ,  Jiyuan Chen  1  3 ,  Shane G Carr ,  Aleksandra Babicheva  1 ,  Amin Izadi  1 ,  Marisela Rodriguez  1 ,  Shamin Rahimi  1 ,  Francesca Balistrieri  1 ,  Shayan Rahimi  1 ,  Tatum Simonson  1 ,  Daniela Valdez-Jasso  5 ,  Patricia A Thistlethwaite  6 ,  John Y-J Shyy  7 ,  Jian Wang  1  3 ,  Ayako Makino  4 ,  Jason X-J Yuan  1
Affiliations
  • 1. Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • 2. Department of Critical Care Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 3. State Key Laboratory of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 4. Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA.
  • 5. Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.
  • 6. Division of Cardiothoracic Surgery, Department of Surgery, University of California, San Diego, La Jolla, California, USA.
  • 7. Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
PMID: 33694155 DOI: 10.1111/bph.15442
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.

Keywords
Ca2+ channel; K+ channel; KCNA5; Pulmonary arterial hypertension; halofuginone; smooth muscle cell; treatment.
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