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Laminar shear stress acts as a switch to regulate divergent functions of NF‐κB in endothelial cells
Author(s) -
Partridge Jason,
Carlsen Harald,
Enesa Karine,
Chaudhury Hera,
Zakkar Mustafa,
Luong Le,
Kinderlerer Anne,
Johns Mike,
Blomhoff Rune,
Mason Justin C.,
Haskard Dorian O.,
Evans Paul C.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-8059com
Subject(s) - proinflammatory cytokine , umbilical vein , nf κb , microbiology and biotechnology , tumor necrosis factor alpha , nfkb1 , shear stress , endothelium , endothelial stem cell , transcription factor , inflammation , chemistry , biology , signal transduction , endocrinology , immunology , biochemistry , materials science , composite material , gene , in vitro
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/cm 2 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 proin‐flammatory transcripts (E‐selectin, VCAM‐1, IL‐8). We demonstrated using assays of nuclear localization, NF‐κB subunit phosphorylation, DNA‐binding, and transcriptional activity that NF‐κB 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 endo‐thelium 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‐κB‐dependent cytoprotective responsiveness while attenuating proinflammatory activation. Thus modulation of NF‐κB 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‐κB in endothelial cells. FASEB J. 21, 3553–3561 (2007)