HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: fj.06-8059comv1 21/13/3553    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Partridge, J. Articles by Evans, P. C. Search for Related Content PubMed PubMed Citation Articles by Partridge, J. Articles by Evans, P. C.

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

This article has been cited by other articles:

				K. Enesa, K. Ito, L. A. Luong, I. Thorbjornsen, C. Phua, Y. To, J. Dean, D. O. Haskard, J. Boyle, I. Adcock, et al. Hydrogen Peroxide Prolongs Nuclear Localization of NF-{kappa}B in Activated Cells by Suppressing Negative Regulatory Mechanisms J. Biol. Chem., July 4, 2008; 283(27): 18582 - 18590. [Abstract] [Full Text] [PDF]

				W. Chen, M. Bacanamwo, and D. G. Harrison Activation of p300 Histone Acetyltransferase Activity Is an Early Endothelial Response to Laminar Shear Stress and Is Essential for Stimulation of Endothelial Nitric-oxide Synthase mRNA Transcription J. Biol. Chem., June 13, 2008; 283(24): 16293 - 16298. [Abstract] [Full Text] [PDF]

				S. Kondo, Y. Tang, E. A. Scheef, N. Sheibani, and C. M. Sorenson Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2 Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1521 - C1530. [Abstract] [Full Text] [PDF]

				A. R. Kinderlerer, F. Ali, M. Johns, E. A. Lidington, V. Leung, J. J. Boyle, S. S. Hamdulay, P. C. Evans, D. O. Haskard, and J. C. Mason KLF2-dependent, Shear Stress-induced Expression of CD59: A NOVEL CYTOPROTECTIVE MECHANISM AGAINST COMPLEMENT-MEDIATED INJURY IN THE VASCULATURE J. Biol. Chem., May 23, 2008; 283(21): 14636 - 14644. [Abstract] [Full Text] [PDF]

				K. Enesa, M. Zakkar, H. Chaudhury, L. A. Luong, L. Rawlinson, J. C. Mason, D. O. Haskard, J. L. E. Dean, and P. C. Evans NF-{kappa}B Suppression by the Deubiquitinating Enzyme Cezanne: A NOVEL NEGATIVE FEEDBACK LOOP IN PRO-INFLAMMATORY SIGNALING J. Biol. Chem., March 14, 2008; 283(11): 7036 - 7045. [Abstract] [Full Text] [PDF]