| Autor: |
Yin, Lei-Miao, Xu, Yu-Dong, Peng, Ling-Ling, Duan, Ting-Ting, Liu, Jia-Yuan, Xu, Zhijian, Wang, Wen-Qian, Guan, Nan, Han, Xiao-Jie, Li, Hai-Yan, Pang, Yu, Wang, Yu, Chen, Zhaoqiang, Zhu, Weiliang, Deng, Linhong, Wu, Ying-Li, Ge, Guang-Bo, Huang, Shuang, Ulloa, Luis, Yang, Yong-Qing |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 2/7/2018, Vol. 10 Issue 427, p1-N.PAG, 10p |
| Abstrakt: |
A transgelin-2 agonist relaxes airway smooth muscle cells and provides therapeutic advantages for asthma. Tickling transgelin-2 for asthma relief: Asthmatics can be refractive to β2-agonists, creating a need for new pathways to be targeted in this disease. Yin et al. discovered that the protein metallothionein-2 was able to reduce airway resistance in rodent asthma models. This improvement was mediated through transgelin-2, and they further studied a transgelin-2 agonist as a new asthma therapeutic. The agonist improved airway function in multiple preclinical asthma models and relaxed human airway smooth muscle cells. These data indicate that activating transgelin-2 for asthma treatment may be more effective than targeting β2-adrenoceptors. 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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