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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4249-4257. Prepublished online as a Blood First Edition Paper on January 23, 2007; DOI 10.1182/blood-2006-07-036020. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2006-07-036020v1 109/10/4249    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fledderus, J. O. Articles by Horrevoets, A. J.G. Search for Related Content PubMed PubMed Citation Articles by Fledderus, J. O. Articles by Horrevoets, A. J.G. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 18, 2006 Accepted January 11, 2007 Prolonged shear stress and KLF2 suppress constitutive pro-inflammatory transcription through inhibition of ATF2 Joost O. Fledderus, Johannes V. van Thienen, Reinier A. Boon, Rob J. Dekker, Jakub Rohlena, Oscar L. Volger, Ann-Pascale J.J. Bijnens, Mat J.A.P. Daemen, Johan Kuiper, Theo J.C. van Berkel, Hans Pannekoek, and Anton J.G. Horrevoets* Dept of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands Dept of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Netherlands Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, Netherlands * Corresponding author; email: a.j.horrevoets{at}amc.uva.nl. Absence of shear stress due to disturbed blood flow at arterial bifurcations and curvatures leads to endothelial dysfunction and pro-inflammatory 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--induced genome-wide expression profiles of human umbilical vein endothelial cells (HUVEC). Cluster analysis confirmed that shear stress induces expression of protective genes including KLF2, eNOS and thrombomodulin, whereas basal expression of TNF--responsive genes was moderately decreased. Promoter analysis of these genes showed enrichment of binding sites for ATF transcription factors, whereas TNF--induced gene expression was mostly NF-B-dependent. Furthermore, human endothelial cells overlying atherosclerotic plaques had increased amounts of phosphorylated nuclear ATF2 compared to endothelium at unaffected sites. In HUVEC, 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 pro-inflammatory 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 pro-inflammatory, atherogenic gene-expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Flow beats inflammation, but not always Bernd R. Binder Blood 2007 109: 4111-4112. [Full Text] [PDF] This article has been cited by other articles: J. Duchene, C. Cayla, S. Vessillier, R. Scotland, K. Yamashiro, F. Lecomte, I. Syed, P. Vo, A. Marrelli, C. Pitzalis, et al. Laminar Shear Stress Regulates Endothelial Kinin B1 Receptor Expression and Function: Potential Implication in Atherogenesis Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1757 - 1763. [Abstract] [Full Text] [PDF] A. Young, W. Wu, W. Sun, H. B. Larman, N. Wang, Y.-S. Li, J. Y. Shyy, S. Chien, and G. Garcia-Cardena Flow Activation of AMP-Activated Protein Kinase in Vascular Endothelium Leads to Kruppel-Like Factor 2 Expression Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1902 - 1908. [Abstract] [Full Text] [PDF] M. Zakkar, K. Van der Heiden, L. A. Luong, H. Chaudhury, S. Cuhlmann, S. S. Hamdulay, R. Krams, I. Edirisinghe, I. Rahman, H. Carlsen, et al. Activation of Nrf2 in Endothelial Cells Protects Arteries From Exhibiting a Proinflammatory State Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1851 - 1857. [Abstract] [Full Text] [PDF] D. E. Conway, Y. Sakurai, D. Weiss, J. D. Vega, W. R. Taylor, H. Jo, S. G. Eskin, C. B. Marcus, and L. V. McIntire Expression of CYP1A1 and CYP1B1 in human endothelial cells: regulation by fluid shear stress Cardiovasc Res, March 1, 2009; 81(4): 669 - 677. [Abstract] [Full Text] [PDF] J. Rohlena, O. L. Volger, J. D. van Buul, L. H.P. Hekking, J. M. van Gils, P. I. Bonta, R. D. Fontijn, J. A. Post, P. L. Hordijk, and A. J.G. Horrevoets Endothelial CD81 is a marker of early human atherosclerotic plaques and facilitates monocyte adhesion Cardiovasc Res, January 1, 2009; 81(1): 187 - 196. [Abstract] [Full Text] [PDF] J. O. Fledderus, R. A. Boon, O. L. Volger, H. Hurttila, S. Yla-Herttuala, H. Pannekoek, A.-L. Levonen, and A. J.G. Horrevoets KLF2 Primes the Antioxidant Transcription Factor Nrf2 for Activation in Endothelial Cells Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1339 - 1346. [Abstract] [Full Text] [PDF] G. R. Romeo and A. 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