title: KLF4 regulates abdominal aortic aneurysm morphology and deletion attenuates aneurysm formation.
abstract: BACKGROUND
  KLF4 mediates inflammatory responses after vascular injury/disease; however, the role of KLF4 in abdominal aortic aneurysms (AAAs) remains unknown. The goals of the present study were to (1) determine the role of KLF4 in experimental AAA; and (2) determine the effect of KLF4 on smooth muscle (SM) cells in AAAs.
  
  
  RESULTS
  KLF4 expression progressively increased at days 3, 7, and 14 after aortic elastase perfusion in C57BL/6 mice. Separately, loss of a KLF4 allele conferred AAA protection using ERTCre+ KLF4 flx/wt mice in the elastase AAA model. In a third set of experiments, SM-specific loss of 1 and 2 KLF4 alleles resulted in progressively greater protection using novel transgenic mice (MYHCre+ flx/flx, flx/wt, and wt/wt) in the elastase AAA model compared with control. Elastin degradation, MAC2, and cytokine production (MCP1, tumor necrosis factor-α, and interleukin-23) were significantly attenuated, whereas α-actin staining was increased in KLF4 knockout mice versus controls. Results were verified in global KLF4 and SM-specific knockout mice using an angiotensin II model of aneurysm formation. KLF4 inhibition with siRNA attenuated downregulation of SM gene expression in vitro, whereas in vivo studies demonstrated that KLF4 binds to promoters of SM genes by chromatin immunoprecipitation analysis. Finally, human aortic aneurysms demonstrated significantly higher KLF4 expression that was localized to SM cells.
  
  
  CONCLUSIONS
  KLF4 plays a critical role in aortic aneurysm formation via effects on SM cells. These results suggest that KLF4 regulates SM cell phenotypic switching and could be a potential therapeutic target for AAA disease.
authors.affiliation: Department of Surgery (M.S., W.F.J., A.W., N.H.P., G.S., G.R.U., G.A.) and The Robert M. Berne Cardiovascular Research Center (G.R.U., G.K.O., G.A.), University of Virginia School of Medicine, Charlottesville, VA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Salmon
authors.forename: William F
authors.initials: WF
authors.lastname: Johnston
authors.forename: Andrew
authors.initials: A
authors.lastname: Woo
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Pope
authors.forename: Gang
authors.initials: G
authors.lastname: Su
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.forename: Gorav
authors.initials: G
authors.lastname: Ailawadi
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D017353:Gene Deletion; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors
keywords: KLF4; aneurysm; myocytes, smooth muscle; transcription factors; vascular biology
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