Science Translational Medicine
Science Translational Medicine
5 years ago

Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance.

Linhong Deng, Yu Wang, Ying-Li Wu, Hai-Yan Li, Weiliang Zhu, Jia-Yuan Liu, Nan Guan, Yong-Qing Yang, Zhijian Xu, Luis Ulloa, Guang-Bo Ge, Zhaoqiang Chen, Yu-Dong Xu, Lei-Miao Yin, Wen-Qian Wang, Ting-Ting Duan, Xiao-Jie Han, Yu Pang, Shuang Huang, Ling-Ling Peng
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.

Publisher URL: http://doi.org/10.1126/scitranslmed.aam8604

DOI: 10.1126/scitranslmed.aam8604

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