title: Myeloid-specific Krüppel-like factor 2 inactivation increases macrophage and neutrophil adhesion and promotes atherosclerosis.
abstract: BACKGROUND
  Hemizygous deficiency of the transcription factor Krüppel-like factor 2 (KLF2) has been shown previously to augment atherosclerosis in hypercholesterolemic mice. However, the cell type responsible for the increased atherosclerosis due to KLF2 deficiency has not been identified. This study examined the consequence of myeloid cell-specific KLF2 inactivation in atherosclerosis.
  
  
  RESULTS
  Cell-specific knockout mice were generated by Cre/loxP recombination. Macrophages isolated from myeloid-specific Klf2 knockout (myeKlf2(-/-)) mice were similar to myeKlf2(+/+) macrophages in response to activation, polarization, and lipid accumulation. However, in comparison to myeKlf2(+/+) macrophages, myeKlf2(-/-) macrophages adhered more robustly to endothelial cells. Neutrophils from myeKlf2(-/-) mice also adhered more robustly to endothelial cells, and fewer myeKlf2(-/-) neutrophils survived in culture over a 24-hour period in comparison with myeKlf2(+/+) neutrophils. When myeKlf2(-/-) mice were mated to Ldlr(-/-) mice and then fed a high fat and high cholesterol diet, significant increase in atherosclerosis was observed in the myeKlf2(-/-)Ldlr(-/-) mice compared with myeKlf2(+/+)Ldlr(-/-) littermates. The increased atherosclerosis in myeKlf2(-/-)Ldlr(-/-) mice was associated with elevated presence of neutrophils and macrophages, with corresponding increase of myeloperoxidase as well as chlorinated and nitrosylated tyrosine epitopes in their lesion areas compared with myeKlf2(+/+)Ldlr(-/-) mice.
  
  
  CONCLUSIONS
  This study documents a role for myeloid KLF2 expression in modulating atherosclerosis. The increased neutrophil accumulation and atherosclerosis progression with myeloid-specific KLF2 deficiency also underscores the importance of neutrophils in promoting vascular oxidative stress and atherosclerosis. Collectively, these results suggest that elevating KLF2 expression may be a novel strategy for prevention and treatment of atherosclerosis.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524. Jerry.Lingrel@uc.edu
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
authors.forename: Robyn
authors.initials: R
authors.lastname: Pilcher-Roberts
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Basford
authors.forename: Palanikumar
authors.initials: P
authors.lastname: Manoharan
authors.forename: Jon
authors.initials: J
authors.lastname: Neumann
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Konaniah
authors.forename: Ramprasad
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Vladimir Y
authors.initials: VY
authors.lastname: Bogdanov
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D002448:Cell Adhesion / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D006937:Hypercholesterolemia / Q000276:immunology / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D018655:Lymphocyte Count; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D014657:Vasculitis / Q000276:immunology / Q000473:pathology
chemical_list: C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors