title: Selective targeting of CREB-binding protein/β-catenin inhibits growth of and extracellular matrix remodelling by airway smooth muscle.
abstract: Asthma is a heterogeneous chronic inflammatory disease, characterized by the development of structural changes (airway remodelling). β-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.
  
  
  
  We assessed the ability of small-molecule compounds that selectively target β-catenin breakdown or its interactions with transcriptional co-activators to inhibit airway smooth muscle remodelling in vitro and in vivo.
  
  
  
  ICG-001, a small-molecule compound that inhibits the β-catenin/CREB-binding protein (CBP) interaction, strongly and dose-dependently inhibited serum-induced smooth muscle growth and TGFβ1-induced production of extracellular matrix components in vitro. Inhibition of β-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, β-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, β-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.
  
  
  
  Together, our findings highlight the importance of β-catenin/CBP signalling in the airways and suggest ICG-001 may be a new therapeutic approach to treat airway smooth muscle remodelling in asthma.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Koopmans
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.
authors.forename: Stijn
authors.initials: S
authors.lastname: Crutzen
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Menzen
authors.affiliation: Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.affiliation: Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Tillie-Louise
authors.initials: TL
authors.lastname: Hackett
authors.affiliation: Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada.|School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.|Asthma, Allergy and Infection Research Cluster, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Knight
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D018927:Anti-Asthmatic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006575:Heterocyclic Compounds, 3-Ring; C492448:ICG 001; D011744:Pyrimidinones; C544261:XAV939; D051176:beta Catenin; D010047:Ovalbumin; D050882:CREB-Binding Protein