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964 results on '"Song, Shanshan"'

36. Halofuginone, a promising drug for treatment of pulmonary hypertension

Author

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

Subjects
Lung, Cardiovascular, Animals, Calcium, Hypertension, Pulmonary, Hypoxia, Mice, Myocytes, Smooth Muscle, Pharmaceutical Preparations, Phosphatidylinositol 3-Kinases, Piperidines, Pulmonary Artery, Quinazolinones, Pulmonary arterial hypertension, halofuginone, treatment, Ca2+ channel, K+ channel, KCNA5, smooth muscle cell, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
Abstract

Background and purposeHalofuginone 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 approachPatch-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 resultsHalofuginone 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 implicationsHalofuginone 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.

Published
2021

44. Activation of the mechanosensitive Ca2+ channel TRPV4 induces endothelial barrier permeability via the disruption of mitochondrial bioenergetics

Author

Lu, Qing, Zemskov, Evgeny A, Sun, Xutong, Wang, Hui, Yegambaram, Manivannan, Wu, Xiaomin, Garcia-Flores, Alejandro, Song, Shanshan, Tang, Haiyang, Kangath, Archana, Cabanillas, Gabriela Zubiate, Yuan, Jason X-J, Wang, Ting, Fineman, Jeffrey R, and Black, Stephen M

Subjects
Biochemistry and Cell Biology, Medicinal and Biomolecular Chemistry, Chemical Sciences, Biological Sciences, Lung, Rare Diseases, Acute Respiratory Distress Syndrome, Patient Safety, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Animals, Endothelial Cells, Endothelium, Energy Metabolism, Humans, Mice, Mitochondria, Permeability, TRPV Cation Channels, VILI, TRPV4, PKC alpha, eNOS, Mitochondrial bioenergetics, Barrier permeability, PKCα, Medical Biochemistry and Metabolomics, Pharmacology and Pharmaceutical Sciences, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS), a refractory lung disease with an unacceptable high mortality rate. Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The specific mechanisms involved in VILI-induced pulmonary capillary leakage, a key pathologic feature of VILI are still far from resolved. The mechanoreceptor, transient receptor potential cation channel subfamily V member 4, TRPV4 plays a key role in the development of VILI through unresolved mechanism. Endothelial nitric oxide synthase (eNOS) uncoupling plays an important role in sepsis-mediated ARDS so in this study we investigated whether there is a role for eNOS uncoupling in the barrier disruption associated with TRPV4 activation during VILI. Our data indicate that the TRPV4 agonist, 4α-Phorbol 12,13-didecanoate (4αPDD) induces pulmonary arterial endothelial cell (EC) barrier disruption through the disruption of mitochondrial bioenergetics. Mechanistically, this occurs via the mitochondrial redistribution of uncoupled eNOS secondary to a PKC-dependent phosphorylation of eNOS at Threonine 495 (T495). A specific decoy peptide to prevent T495 phosphorylation reduced eNOS uncoupling and mitochondrial redistribution and preserved PAEC barrier function under 4αPDD challenge. Further, our eNOS decoy peptide was able to preserve lung vascular integrity in a mouse model of VILI. Thus, we have revealed a functional link between TRPV4 activation, PKC-dependent eNOS phosphorylation at T495, and EC barrier permeability. Reducing pT495-eNOS could be a new therapeutic approach for the prevention of VILI.

Published
2021

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