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Laminar shear stress acts as a switch to regulate divergent functions of NF-B in endothelial cells

Jason Partridge^*, Harald Carlsen, Karine Enesa^*, Hera Chaudhury^*, Mustafa Zakkar^*, Le Luong^*, Anne Kinderlerer^*, Mike Johns^*, Rune Blomhoff, Justin C. Mason^*, Dorian O. Haskard^* and Paul C. Evans^*,1

^* BHF Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College London, London, UK; and

Institute for Nutrition Research, University of Oslo, Oslo, Norway

¹Correspondence: BHF Cardiovascular Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Rd., London W12 ONN, UK. E-mail: paul.evans{at}imperial.ac.uk

Regions of the arterial tree exposed to laminar flow, which exerts high shear stress, are protected from inflammation, endothelial cell (EC) death and atherosclerosis. TNF activates NF-B transcription factors, which potentially exert dual functions by inducing both proinflammatory and cytoprotective transcripts. We assessed whether laminar shear stress protects EC by modulating NF-B function. Human umbilical vein EC (HUVEC) were cultured under shear stress (12 dynes/cm² for 16 h) using a parallel-plate flow chamber or were maintained in static conditions. Comparative real-time PCR revealed that preshearing significantly alters transcriptional responses to TNF by enhancing the expression of cytoprotective molecules (Bcl-2, MnSOD, GADD45ß, A1) and suppressing proinflammatory transcripts (E-selectin, VCAM-1, IL-8). We demonstrated using assays of nuclear localization, NF-B subunit phosphorylation, DNA-binding, and transcriptional activity that NF-B is activated by TNF in presheared HUVEC. Furthermore, a specific inhibitor revealed that NF-B is essential for the induction of cytoprotective transcripts in presheared EC. Finally, we observed that NF-B can be activated in vascular endothelium exposed to laminar shear stress in NF-B-luciferase reporter mice, thus validating our cell culture experiments. We conclude that shear stress primes EC for enhanced NF-B-dependent cytoprotective responsiveness while attenuating proinflammatory activation. Thus modulation of NF-B function may underlie the atheroprotective effects of laminar shear stress.—Partridge, J., Carlsen, H., Enesa, K., Chaudhury, H., Zakkar, M., Luong, L., Kinderlerer, A., Johns, M., Blomhoff, R., Mason, J. C., Haskard, D. O., Evans, P. C. Laminar shear stress acts as a switch to regulate divergent functions of NF-B in endothelial cells.

Key Words: atherosclerosis • blood flow • proinflammatory activation • cytoprotection

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