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B in endothelial cells
E-mail contact: paul.evans@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, GADD45
, 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.
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