Open AccessDabigatran ameliorates airway smooth muscle remodeling in asthma by modulating Yes‐associated protein
Author(s) -
Deng Zhenan,
Xie Haojun,
Cheng Weiying,
Zhang Meihong,
Liu Jie,
Huo Yating,
Liao Yulin,
Cheng Yuanxiong
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15485
Subject(s) - dabigatran , thrombin , ctgf , medicine , rhoa , microbiology and biotechnology , pharmacology , cancer research , chemistry , signal transduction , growth factor , biology , receptor , warfarin , atrial fibrillation , platelet
Accumulating evidence indicates that thrombin, the major effector of the coagulation cascade, plays an important role in the pathogenesis of asthma. Interestingly, dabigatran, a drug used in clinical anticoagulation, directly inhibits thrombin activity. The aim of this study was to investigate the effects and mechanisms of dabigatran on airway smooth muscle remodeling in vivo and in vitro. Here, we found that dabigatran attenuated inflammatory pathology, mucus production, and collagen deposition in the lungs of asthmatic mice. Additionally, dabigatran suppressed Yes‐associated protein (YAP) activation in airway smooth muscle of asthmatic mice. In human airway smooth muscle cells (HASMCs), dabigatran not only alleviated thrombin‐induced proliferation, migration and up‐regulation of collagen I, α‐SMA, CTGF and cyclin D1, but also inhibited thrombin‐induced YAP activation, while YAP activation mediated thrombin‐induced HASMCs remodeling. Mechanistically, thrombin promoted actin stress fibre polymerization through the PAR1/RhoA/ROCK/MLC2 axis to activate YAP and then interacted with SMAD2 in the nucleus to induce downstream target genes, ultimately aggravating HASMCs remodeling. Our study provides experimental evidence that dabigatran ameliorates airway smooth muscle remodeling in asthma by inhibiting YAP signalling, and dabigatran may have therapeutic potential for the treatment of asthma.