title: KLF2 primes the antioxidant transcription factor Nrf2 for activation in endothelial cells.
abstract: OBJECTIVE
  Atheroprotective blood flow induces expression of anti-inflammatory Krüppel-like factor 2 (KLF2) and activates antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in vascular endothelium. Previously, we obtained KLF2-induced gene expression profiles in ECs, containing several Nrf2 target genes. Our aim was to investigate the role of KLF2 in shear stress-mediated activation of Nrf2 in human umbilical vein endothelial cells (HUVECs).
  
  
  RESULTS
  Expression of Nrf2 and its targets NAD(P)H dehydrogenase quinone 1 (NQO1) and heme oxygenase (HO-1) was elevated by shear and KLF2. KLF2 knockdown showed that shear-induced expression of NQO1 but not Nrf2 was dependent on KLF2. KLF2 overexpression in absence of flow resulted in more efficient activation of Nrf2 by tert-butyl hydroquinone (tBHQ) through enhanced nuclear localization, and promoted expression of a large panel of Nrf2-dependent genes resulting in superior protection against oxidative stress. Comparison of shear-, KLF2-, and Nrf2-induced transcriptomes showed that the majority of shear-modulated gene sets is influenced by KLF2 or Nrf2.
  
  
  CONCLUSIONS
  We report that KLF2 substantially enhances antioxidant activity of Nrf2 by increasing its nuclear localization and activation. The synergistic activity of these two transcription factors forms a major contribution to the shear stress-elicited transcriptome in endothelial cells.
authors.affiliation: Department of Molecular Cell Biology and Immunology, Room B244, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Joost O
authors.initials: JO
authors.lastname: Fledderus
authors.forename: Reinier A
authors.initials: RA
authors.lastname: Boon
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Volger
authors.forename: Hanna
authors.initials: H
authors.lastname: Hurttila
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Hans
authors.initials: H
authors.lastname: Pannekoek
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
authors.forename: Anton J G
authors.initials: AJ
authors.lastname: Horrevoets
mesh_terms: D021581:Active Transport, Cell Nucleus; D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004790:Enzyme Induction; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D011673:Pulsatile Flow; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013314:Stress, Mechanical; D014162:Transfection; D015854:Up-Regulation; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D000975:Antioxidants; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D034741:RNA, Small Interfering; D020122:tert-Butylhydroperoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human