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Halofuginone, a promising drug for treatment of pulmonary hypertension
- Source :
- Br J Pharmacol, British journal of pharmacology, vol 178, iss 17
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
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 Ca(2+) channels (VDCCs) in pulmonary artery smooth muscle cells (PASMCs). Digital fluorescence microscopy was used to measure intracellular Ca(2+) concentration in PASMCs. Isolated perfused and ventilated mouse lungs were used to measure pulmonary artery pressure (PAP). Mice exposed to hypoxia (10% O(2)) for 4 weeks were used as model of HPH for in vivo experiments. KEY RESULTS: 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 Ca(2+) entry in HEK cells transfected with calcium-sensing receptor gene and attenuated store-operated Ca(2+) 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 K(v) channels and blocking VDCC and receptor-operated and store-operated Ca(2+) 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.
- Subjects :
- K+ channel
Hypertension, Pulmonary
Myocytes, Smooth Muscle
Vasodilation
Pulmonary Artery
Pharmacology
Pulmonary arterial hypertension
Cardiovascular
Article
KCNA5
Mice
Phosphatidylinositol 3-Kinases
halofuginone
Piperidines
Smooth Muscle
In vivo
medicine.artery
Hypoxic pulmonary vasoconstriction
medicine
Animals
Pharmacology & Pharmacy
Hypoxia
Lung
smooth muscle cell
Quinazolinones
Myocytes
Ca2+ channel
treatment
Halofuginone
Chemistry
HEK 293 cells
Pulmonary
Pharmacology and Pharmaceutical Sciences
Hypoxia (medical)
medicine.disease
Pulmonary hypertension
Pharmaceutical Preparations
Hypertension
Pulmonary artery
Calcium
medicine.symptom
medicine.drug
Subjects
Details
- ISSN :
- 14765381 and 00071188
- Volume :
- 178
- Database :
- OpenAIRE
- Journal :
- British Journal of Pharmacology
- Accession number :
- edsair.doi.dedup.....499ef3d96595495d79afa1e34ae53292