Pritesh P Jain1, Tengteng Zhao1, Mingmei Xiong1,2, Shanshan Song, Ning Lai1,3, Qiuyu Zheng4, Jiyuan Chen1,3, Shane G Carr, Aleksandra Babicheva1, Amin Izadi1, Marisela Rodriguez1, Shamin Rahimi1, Francesca Balistrieri1, Shayan Rahimi1, Tatum Simonson1, Daniela Valdez-Jasso5, Patricia A Thistlethwaite6, John Y-J Shyy7, Jian Wang1,3, Ayako Makino4, Jason X-J Yuan1. 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.
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.
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.
Authors: Ziyi Wang; Jiyuan Chen; Aleksandra Babicheva; Pritesh P Jain; Marisela Rodriguez; Ramon J Ayon; Keeley S Ravellette; Linda Wu; Francesca Balistrieri; Haiyang Tang; Xiaomin Wu; Tengteng Zhao; Stephen M Black; Ankit A Desai; Joe G N Garcia; Xin Sun; John Y-J Shyy; Daniela Valdez-Jasso; Patricia A Thistlethwaite; Ayako Makino; Jian Wang; Jason X-J Yuan Journal: Am J Physiol Cell Physiol Date: 2021-10-20 Impact factor: 5.282
Authors: Xin Zhen; Esteban A Moya; Mary Gautane; Huayi Zhao; Elijah S Lawrence; Wanjun Gu; Laura A Barnes; Jason X-J Yuan; Pritesh P Jain; Mingmei Xiong; Pablo Catalan Serra; Luu V Pham; Atul Malhotra; Tatum S Simonson; Omar A Mesarwi Journal: Sleep Date: 2022-06-13 Impact factor: 6.313
Authors: Pritesh P Jain; Ning Lai; Mingmei Xiong; Jiyuan Chen; Aleksandra Babicheva; Tengteng Zhao; Sophia Parmisano; Manjia Zhao; Cole Paquin; Moreen Matti; Ryan Powers; Angela Balistrieri; Nick H Kim; Daniela Valdez-Jasso; Patricia A Thistlethwaite; John Y-J Shyy; Jian Wang; Joe G N Garcia; Ayako Makino; Jason X-J Yuan Journal: Am J Physiol Lung Cell Mol Physiol Date: 2021-10-27 Impact factor: 6.011