- Title
- Selective targeting of CREB-binding protein/ß-catenin inhibits growth of and extracellular matrix remodelling by airway smooth muscle
- Creator
- Koopmans, Tim; Crutzen, Stijn; Menzen, Mark H.; Halayko, Andrew J.; Hackett, Tillie-Louise; Knight, Darryl A.; Gosens, Reinoud
- Relation
- British Journal of Pharmacology Vol. 173, Issue 23, p. 3327-3341
- Publisher Link
- http://dx.doi.org/10.1111/bph.13620
- Publisher
- John Wiley & Sons
- Resource Type
- journal article
- Date
- 2016
- Description
- Background and Purpose: Asthma is a heterogeneous chronic inflammatory disease, characterized by the development of structural changes (airway remodelling). ß-catenin, a transcriptional co-activator, is fundamentally involved in airway smooth muscle growth and may be a potential target in the treatment of airway smooth muscle remodelling. Experimental Approach: We assessed the ability of small-molecule compounds that selectively target ß-catenin breakdown or its interactions with transcriptional co-activators to inhibit airway smooth muscle remodelling in vitro and in vivo. Key Results: ICG-001, a small-molecule compound that inhibits the ß-catenin/CREB-binding protein (CBP) interaction, strongly and dose-dependently inhibited serum-induced smooth muscle growth and TGFß1-induced production of extracellular matrix components in vitro. Inhibition of ß-catenin/p300 interactions using IQ-1 or inhibition of tankyrase 1/2 using XAV-939 had considerably less effect. In a mouse model of allergic asthma, ß-catenin expression in the smooth muscle layer was found to be unaltered in control versus ovalbumin-treated animals, a pattern that was found to be similar in smooth muscle within biopsies taken from asthmatic and non-asthmatic donors. However, ß-catenin target gene expression was highly increased in response to ovalbumin; this effect was prevented by topical treatment with ICG-001. Interestingly, ICG-001 dose-dependently reduced airway smooth thickness after repeated ovalbumin challenge, but had no effect on the deposition of collagen around the airways, mucus secretion or eosinophil infiltration. Conclusions and Implications: Together, our findings highlight the importance of ß-catenin/CBP signalling in the airways and suggest ICG-001 may be a new therapeutic approach to treat airway smooth muscle remodelling in asthma.
- Subject
- asthma; chronic inflammatory diseases; ß-catenin; airway smooth muscle remodelling
- Identifier
- http://hdl.handle.net/1959.13/1325624
- Identifier
- uon:25315
- Identifier
- ISSN:0007-1188
- Language
- eng
- Reviewed
- Hits: 7962
- Visitors: 6745
- Downloads: 0
| Thumbnail | File | Description | Size | Format |
|---|