Prolonged shear stress and KLF2 suppress constitutive proinflammatory 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, Anton J.G. Horrevoets*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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-α-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-α-responsive genes was moderately decreased. Promoter analysis of these genes showed enrichment of binding sites for ATF transcription factors, whereas TNF-α-induced gene expression was mostly NF-κB 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.

Original languageEnglish
Pages (from-to)4249-4257
Number of pages9
JournalBlood
Volume109
Issue number10
DOIs
Publication statusPublished - 15 May 2007

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