title: Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2.
abstract: Absence of shear stress due to disturbed blood flow at arterial bifurcations and curvatures leads to endothelial dysfunction and proinflammatory gene expression, ultimately resulting in atherogenesis. KLF2 has recently been implicated as a transcription factor involved in mediating the anti-inflammatory effects of flow. We investigated the effect of shear on basal and TNF-alpha-induced genomewide expression profiles of human umbilical vein endothelial cells (HUVECs). Cluster analysis confirmed that shear stress induces expression of protective genes including KLF2, eNOS, and thrombomodulin, whereas basal expression of TNF-alpha-responsive genes was moderately decreased. Promoter analysis of these genes showed enrichment of binding sites for ATF transcription factors, whereas TNF-alpha-induced gene expression was mostly NF-kappaB dependent. Furthermore, human endothelial cells overlying atherosclerotic plaques had increased amounts of phosphorylated nuclear ATF2 compared with endothelium at unaffected sites. In HUVECs, a dramatic reduction of nuclear binding activity of ATF2 was observed under shear and appeared to be KLF2 dependent. Reduction of ATF2 with siRNA potently suppressed basal proinflammatory gene expression under no-flow conditions. In conclusion, we demonstrate that shear stress and KLF2 inhibit nuclear activity of ATF2, providing a potential mechanism by which endothelial cells exposed to laminar flow are protected from basal proinflammatory, atherogenic gene expression.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joost O
authors.initials: JO
authors.lastname: Fledderus
authors.forename: Johannes V
authors.initials: JV
authors.lastname: van Thienen
authors.forename: Reinier A
authors.initials: RA
authors.lastname: Boon
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Dekker
authors.forename: Jakub
authors.initials: J
authors.lastname: Rohlena
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Volger
authors.forename: Ann-Pascale J J
authors.initials: AP
authors.lastname: Bijnens
authors.forename: Mat J A P
authors.initials: MJ
authors.lastname: Daemen
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Hans
authors.initials: H
authors.lastname: Pannekoek
authors.forename: Anton J G
authors.initials: AJ
authors.lastname: Horrevoets
mesh_terms: D051698:Activating Transcription Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016000:Cluster Analysis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013314:Stress, Mechanical; D013997:Time Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases