| Autor: |
Partridge, Jason, Carlsen, Harald, Enesa, Karine, Chaudhury, Hera, Zakkar, Mustafa, Le Luong, Kinderlerer, Anne, Johns, Mike, Blomhoff, Rune, Mason, Justin C., Haskard, Dorian O., Evans, Paul C. |
| Předmět: |
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| Zdroj: |
FASEB Journal; Nov2007, Vol. 21 Issue 13, p3553-3561, 9p, 1 Chart, 7 Graphs |
| Abstrakt: |
Regions of the arterial tree exposed to laminar flow, which exerts high shear stress, are protected from inflammation, endothelial cell (EC) death and atherosclerosis. TNFα activates NF-κB 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-κB 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 TNFα by enhancing the expression of cytoprotective molecules (Bcl-2, MnSOD, GADD45β, A1) and suppressing proinflammatory transcripts (E-selectin, VCAM-1, IL-8). We demonstrated using assays of nuclear localization, NF-KB subunit phosphorylation, DNA-binding, and transcriptional activity that NF-KB is activated by TNFα in presheared HUVEC. Furthermore, a specific inhibitor revealed that NF-κB is essential for the induction of cytoprotective transcripts in presheared EC. Finally, we observed that NF-κB can be activated in vascular endothelium exposed to laminar shear stress in NF-κB-luciferase reporter mice, thus validating our cell culture experiments. We conclude that shear stress primes EC for enhanced NF-KB-dependent cytoprotective responsiveness while attenuating proinflammatory activation. Thus modulation of NF-KB function may underlie the atheroprotecfive effects of laminar shear stress. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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