title: Shear stress sustains atheroprotective endothelial KLF2 expression more potently than statins through mRNA stabilization.
abstract: OBJECTIVE
  The transcription factor KLF2 is considered an important mediator of the anti-inflammatory and anti-thrombotic properties of the endothelium. KLF2 is absent from low-shear, atherosclerosis-prone sites of the vascular tree but is induced by HMG-CoA reductase inhibitors (statins) in vitro. We studied KLF2-dependent induction of important determinants of the atheroprotective status of the endothelium to determine whether pharmacological intervention, e.g. by statins, can potentially replace shear stress.
  
  
  METHODS
  Shear stress and statin effects in combination with TNF-alpha were determined in human umbilical vein endothelial cells by quantitative measurements of the steady-state levels and stability of mRNA for KLF2 and its downstream target genes thrombomodulin (TM) and endothelial nitric oxide synthase (eNOS).
  
  
  RESULTS
  We demonstrate that prolonged shear stress has a potential that is superior to that of statins to induce the KLF2-dependent expression of eNOS and TM, especially in the presence of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). These effects can be attributed to the sustained stabilization of KLF2 mRNA by shear, leading to an increased KLF2 protein expression and concomitant strong induction of KLF2 downstream targets. The stabilization of KLF2 mRNA is demonstrated to be dependent on signaling involving phosphoinositide 3-kinase (PI3K).
  
  
  CONCLUSIONS
  The stabilization of KLF2 steady-state levels, as induced by prolonged shear stress but not by statins, may be essential for sustaining the quiescent, atheroprotective status of the vascular endothelium under inflammatory conditions.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Johannes V
authors.initials: JV
authors.lastname: van Thienen
authors.forename: Joost O
authors.initials: JO
authors.lastname: Fledderus
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Dekker
authors.forename: Jakub
authors.initials: J
authors.lastname: Rohlena
authors.forename: Gerben A
authors.initials: GA
authors.lastname: van Ijzendoorn
authors.forename: Neeltje A
authors.initials: NA
authors.lastname: Kootstra
authors.forename: Hans
authors.initials: H
authors.lastname: Pannekoek
authors.forename: Anton J G
authors.initials: AJ
authors.lastname: Horrevoets
mesh_terms: D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007249:Inflammation; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002867:Chromones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt