title: Smooth muscle-selective inhibition of nuclear factor-κB attenuates smooth muscle phenotypic switching and neointima formation following vascular injury.
abstract: BACKGROUND
  Vascular proliferative diseases such as atherosclerosis are inflammatory disorders involving multiple cell types including macrophages, lymphocytes, endothelial cells, and smooth muscle cells (SMCs). Although activation of the nuclear factor-κB (NF-κB) pathway in vessels has been shown to be critical for the progression of vascular diseases, the cell-autonomous role of NF-κB within SMCs has not been fully understood.
  
  
  RESULTS
  We generated SMC-selective truncated IκB expressing (SM22α-Cre/IκBΔN) mice, in which NF-κB was inhibited selectively in SMCs, and analyzed their phenotype following carotid injury. Results showed that neointima formation was markedly reduced in SM22α-Cre/IκBΔN mice after injury. Although vascular injury induced downregulation of expression of SMC differentiation markers and myocardin, a potent activator of SMC differentiation markers, repression of these markers and myocardin was attenuated in SM22α-Cre/IκBΔN mice. Consistent with these findings, NF-κB activation by interleukin-1β (IL-1β) decreased expression of SMC differentiation markers as well as myocardin in cultured SMCs. Inhibition of NF-κB signaling by BAY 11-7082 attenuated repressive effects of IL-1β. Of interest, Krüppel-like factor 4 (Klf4), a transcription factor critical for regulating SMC differentiation and proliferation, was also involved in IL-1β-mediated myocardin repression. Promoter analyses and chromatin immunoprecipitation assays revealed that NF-κB repressed myocardin by binding to the myocardin promoter region in concert with Klf4.
  
  
  CONCLUSIONS
  These results provide novel evidence that activation of the NF-κB pathway cell-autonomously mediates SMC phenotypic switching and contributes to neointima formation following vascular injury.
authors.affiliation: Apheresis and Dialysis Center, School of Medicine, Keio University, Tokyo, Japan. tayoshida-npr@umin.ac.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Maho
authors.initials: M
authors.lastname: Yamashita
authors.forename: Chihiro
authors.initials: C
authors.lastname: Horimai
authors.forename: Matsuhiko
authors.initials: M
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D005812:Genes, Switch; D020672:I-kappa B Proteins / Q000235:genetics; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D058426:Neointima / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D015534:Trans-Activators / Q000235:genetics; D057772:Vascular System Injuries / Q000150:complications* / Q000235:genetics*; D000099251:Myocardin
chemical_list: D020672:I-kappa B Proteins; D000090062:Kruppel-Like Factor 4; D016328:NF-kappa B; D009687:Nuclear Proteins; D015534:Trans-Activators; D000099251:Myocardin; C000715468:Klf4 protein, mouse
keywords: Klf4; myocardin; nuclear factor‐κB; smooth muscle cells