title: XAV939 Inhibits Intima Formation by Decreasing Vascular Smooth Muscle Cell Proliferation and Migration Through Blocking Wnt Signaling.
abstract: BACKGROUND
  Excessive proliferation, migration, and oxidative stress of vascular smooth muscle cells (VSMCs) are key mechanisms involved in intima formation, which is the basic pathological process of in stent restenosis. This study aims at exploring the role of XAV939 in proliferation, migration, and reactive oxygen species (ROS) generation of VSMCs, and hence evaluating its effects on intima formation.
  
  
  METHODS
  Carotid artery ligation models for C57BL/6 mice were established and gave them different intervention: saline, XAV939, Axin2 overexpression adenovirus, and negative control adenovirus. The intima formation was assayed by intima area and intima/media ratio. To investigate the underlying mechanisms, primary rat VSMCs were cultured and treated with XAV939 and platelet-derived growth factor-BB. EdU, direct cell counting, cell wound-healing assay, and flow cytometry were used to measure proliferation, migration, cell cycle, apoptosis, and ROS generation of VSMCs, respectively. By Western blot, we examined proliferating cell nuclear antigen, Cyclin D1, Cyclin E, p21, β-actin, JNK, phosphorylated JNK, Axin2 and β-catenin expression. Immunofluorescence staining and confocal microscopy were conducted to detect translocation of β-catenin.
  
  
  RESULTS
  XAV939 inhibited intima formation, which was exhibited by the loss of intima area and I/M ratio and attenuated proliferation, migration, and ROS generation, as well as promoted cell cycle arrest of VSMCs. Specifically, XAV939 inhibited Wnt pathway.
  
  
  CONCLUSIONS
  XAV939 attenuates intima formation because of its inhibition of proliferation, migration, and apoptosis of VSMCs through suppression of Wnt signaling pathway.
authors.affiliation: Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Luoman
authors.initials: L
authors.lastname: Chen
authors.forename: Jianhui
authors.initials: J
authors.lastname: Zhuang
authors.forename: Shekhar
authors.initials: S
authors.lastname: Singh
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Mengting
authors.initials: M
authors.lastname: Xiong
authors.forename: Dachun
authors.initials: D
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Pang
authors.forename: Yawei
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiankai
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000502:physiology
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D017382:Reactive Oxygen Species; C544261:XAV939