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

@article{partridge2007, abstract = {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{alpha} activates NF-{kappa}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-{kappa}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{alpha} by enhancing the expression of cytoprotective molecules (Bcl-2, MnSOD, GADD45{beta}, A1) and suppressing proinflammatory transcripts (E-selectin, VCAM-1, IL-8). We demonstrated using assays of nuclear localization, NF-{kappa}B subunit phosphorylation, DNA-binding, and transcriptional activity that NF-{kappa}B is activated by TNF{alpha} in presheared HUVEC. Furthermore, a specific inhibitor revealed that NF-{kappa}B is essential for the induction of cytoprotective transcripts in presheared EC. Finally, we observed that NF-{kappa}B can be activated in vascular endothelium exposed to laminar shear stress in NF-{kappa}B-luciferase reporter mice, thus validating our cell culture experiments. We conclude that shear stress primes EC for enhanced NF-{kappa}B-dependent cytoprotective responsiveness while attenuating proinflammatory activation. Thus modulation of NF-{kappa}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-{kappa}B in endothelial cells. 10.1096/fj.06-8059com}, author = {Partridge, Jason and Carlsen, Harald and Enesa, Karine and Chaudhury, Hera and Zakkar, Mustafa and Luong, Le and Kinderlerer, Anne and Johns, Mike and Blomhoff, Rune and Mason, Justin C. and Haskard, Dorian O. and Evans, Paul C.}, citeulike-article-id = {2429926}, citeulike-linkout-0 = {http://dx.doi.org/10.1096/fj.06-8059com}, citeulike-linkout-1 = {http://www.fasebj.org/cgi/content/abstract/21/13/3553}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17557931}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17557931}, day = {1}, doi = {10.1096/fj.06-8059com}, journal = {FASEB J.}, keywords = {endothelial, nfkb, wss}, month = {November}, number = {13}, pages = {3553--3561}, posted-at = {2008-02-26 15:05:35}, priority = {2}, title = {Laminar shear stress acts as a switch to regulate divergent functions of NF-{kappa}B in endothelial cells}, url = {http://dx.doi.org/10.1096/fj.06-8059com}, volume = {21}, year = {2007} }

TY - JOUR ID - partridge2007 L3 - citeulike-article-id:2429926 N2 - 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{alpha} activates NF-{kappa}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-{kappa}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{alpha} by enhancing the expression of cytoprotective molecules (Bcl-2, MnSOD, GADD45{beta}, A1) and suppressing proinflammatory transcripts (E-selectin, VCAM-1, IL-8). We demonstrated using assays of nuclear localization, NF-{kappa}B subunit phosphorylation, DNA-binding, and transcriptional activity that NF-{kappa}B is activated by TNF{alpha} in presheared HUVEC. Furthermore, a specific inhibitor revealed that NF-{kappa}B is essential for the induction of cytoprotective transcripts in presheared EC. Finally, we observed that NF-{kappa}B can be activated in vascular endothelium exposed to laminar shear stress in NF-{kappa}B-luciferase reporter mice, thus validating our cell culture experiments. We conclude that shear stress primes EC for enhanced NF-{kappa}B-dependent cytoprotective responsiveness while attenuating proinflammatory activation. Thus modulation of NF-{kappa}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-{kappa}B in endothelial cells. 10.1096/fj.06-8059com IS - 13 JF - FASEB J. EP - 3561 TI - Laminar shear stress acts as a switch to regulate divergent functions of NF-{kappa}B in endothelial cells VL - 21 SP - 3553 KW - endothelial KW - nfkb KW - wss AU - Partridge, Jason AU - Carlsen, Harald AU - Enesa, Karine AU - Chaudhury, Hera AU - Zakkar, Mustafa AU - Luong, Le AU - Kinderlerer, Anne AU - Johns, Mike AU - Blomhoff, Rune AU - Mason, Justin AU - Haskard, Dorian AU - Evans, Paul PY - 2007/11/01/ UR - http://dx.doi.org/10.1096/fj.06-8059com ER -