Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance
| Autor: | Linhong Deng, Ting Ting Duan, Yu Dong Xu, Weiliang Zhu, Wen Qian Wang, Ying Li Wu, Zhaoqiang Chen, Hai Yan Li, Guang Bo Ge, Jia Yuan Liu, Yu Pang, Luis Ulloa, Xiao Jie Han, Yong-Qing Yang, Zhijian Xu, Yu Wang, Lei-Miao Yin, Ling Ling Peng, Nan Guan, Shuang Huang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
RHOA medicine.drug_class Muscle Proteins Pharmacology Article Dephosphorylation Mice 03 medical and health sciences 0302 clinical medicine In vivo Bronchodilator Animals Medicine Lung Asthma Mice Knockout biology business.industry Microfilament Proteins General Medicine medicine.disease Molecular Docking Simulation Disease Models Animal Ovalbumin 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Phosphorylation business |
| Zdroj: | Science Translational Medicine. 10 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | There is a clinical need for new bronchodilator drugs in asthma, because more than half of asthmatic patients do not receive adequate control with current available treatments. We report that inhibition of metallothionein-2 protein expression in lung tissues causes the increase of pulmonary resistance. Conversely, metallothionein-2 protein is more effective than β2-agonists in reducing pulmonary resistance in rodent asthma models, alleviating tension in tracheal spirals, and relaxing airway smooth muscle cells (ASMCs). Metallothionein-2 relaxes ASMCs via transgelin-2 (TG2) and induces dephosphorylation of myosin phosphatase target subunit 1 (MYPT1). We identify TSG12 as a nontoxic, specific TG2-agonist that relaxes ASMCs and reduces asthmatic pulmonary resistance. In vivo, TSG12 reduces pulmonary resistance in both ovalbumin- and house dust mite–induced asthma in mice. TSG12 induces RhoA phosphorylation, thereby inactivating the RhoA-ROCK-MYPT1-MLC pathway and causing ASMCs relaxation. TSG12 is more effective than β2-agonists in relaxing human ASMCs and pulmonary resistance with potential clinical advantages. These results suggest that TSG12 could be a promising therapeutic approach for treating asthma. |
| Databáze: | OpenAIRE |
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