Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance

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

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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 -2-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 -2-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.

Original languageEnglish (US)
Article numbereaam8604
JournalScience translational medicine
Volume10
Issue number427
DOIs
StatePublished - Feb 7 2018

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Yin, L. M., Xu, Y. D., Peng, L. L., Duan, T. T., Liu, J. Y., Xu, Z., Wang, W. Q., Guan, N., Han, X. J., Li, H. Y., Pang, Y., Wang, Y., Chen, Z., Zhu, W., Deng, L., Wu, Y. L., Ge, G. B., Huang, S., Ulloa, L., & Yang, Y. Q. (2018). Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance. Science translational medicine, 10(427), [eaam8604]. https://doi.org/10.1126/scitranslmed.aam8604