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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • February 7, 2018

Published In

Volume / Issue

  • 10 / 427

PubMed ID

  • 29437149

Pubmed Central ID

  • 29437149

Electronic International Standard Serial Number (EISSN)

  • 1946-6242

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.aam8604

Language

  • eng

Conference Location

  • United States