KLF2-induced actin shear fibers control both alignment to flow and JNK signaling in vascular endothelium

• Published in: Blood Vol. 115; no. 12; pp. 2533 - 2542
• Main Authors: Boon, Reinier A., Leyen, Thomas A., Fontijn, Ruud D., Fledderus, Joost O., Baggen, Josefien M.C., Volger, Oscar L., van Nieuw Amerongen, Geerten P., Horrevoets, Anton J.G.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 25.03.2010; Americain Society of Hematology
• Subjects: Actin Cytoskeleton - metabolism; Activating Transcription Factor 2 - metabolism; Animals; Aorta - cytology; Biological and medical sciences; Cells, Cultured; Endothelial Cells - cytology; Endothelial Cells - metabolism; Femoral Artery - cytology; Hematologic and hematopoietic diseases; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; MAP Kinase Signaling System - physiology; Medical sciences; Phosphorylation - physiology; Rats; Regional Blood Flow - physiology; rho-Associated Kinases - metabolism; Saphenous Vein - cytology; Stress, Mechanical; Transduction, Genetic; Umbilical Veins - cytology; Shear; Hematology; Nutrition; Enzyme; Transferases; Fiber; Mitogen-activated protein kinase; Contractile protein; Krppel-like factor 2; Feeding; Endothelium; Signal transduction; Diet; Actin; Blood vessel; Circulatory system
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-06-228726

The shear stress–induced transcription factor Krüppel-like factor 2 (KLF2) confers antiinflammatory properties to endothelial cells through the inhibition of activator protein 1, presumably by interfering with mitogen-activated protein kinase (MAPK) cascades. To gain insight into the regulation of these cascades by KLF2, we used antibody arrays in combination with time-course mRNA microarray analysis. No gross changes in MAPKs were detected; rather, phosphorylation of actin cytoskeleton-associated proteins, including focal adhesion kinase, was markedly repressed by KLF2. Furthermore, we demonstrate that KLF2-mediated inhibition of Jun NH2-terminal kinase (JNK) and its downstream targets ATF2/c-Jun is dependent on the cytoskeleton. Specifically, KLF2 directs the formation of typical short basal actin filaments, termed shear fibers by us, which are distinct from thrombin- or tumor necrosis factor-α–induced stress fibers. KLF2 is shown to be essential for shear stress–induced cell alignment, concomitant shear fiber assembly, and inhibition of JNK signaling. These findings link the specific effects of shear-induced KLF2 on endothelial morphology to the suppression of JNK MAPK signaling in vascular homeostasis via novel actin shear fibers.