Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2

• Published in: Blood Vol. 109; no. 10; pp. 4249 - 4257
• Main Authors: Fledderus, Joost O., van Thienen, Johannes V., Boon, Reinier A., Dekker, Rob J., Rohlena, Jakub, Volger, Oscar L., Bijnens, Ann-Pascale J.J., Daemen, Mat J.A.P., Kuiper, Johan, van Berkel, Theo J.C., Pannekoek, Hans, Horrevoets, Anton J.G.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.05.2007; The Americain Society of Hematology
• Subjects: Activating Transcription Factor 2 - antagonists & inhibitors; Activating Transcription Factor 2 - genetics; Activating Transcription Factor 2 - metabolism; Atherosclerosis - genetics; Biological and medical sciences; Cell Nucleus - metabolism; Cells, Cultured; Cluster Analysis; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Gene Expression Regulation - drug effects; Hematologic and hematopoietic diseases; Humans; Inflammation - genetics; Kruppel-Like Transcription Factors - physiology; Medical sciences; Phosphorylation; Protein Kinases - metabolism; RNA, Small Interfering - pharmacology; Stress, Mechanical; Time Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha - pharmacology; Transcription factor ATF2; Hematology; Transcription; Shear stress; Inflammation; Inhibitor; Lung Kruppel like factor; Prolonged
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-07-036020

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.