Journal
CIRCULATION RESEARCH
Volume 103, Issue 6, Pages 671-679Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.182097
Keywords
endothelial cell dysfunction; extracellular matrix; fluid shear stress; NF-kappa B; reactive oxygen species
Funding
- United States Public Health Service [RO1 HL75092, HL80956, HL082836]
- American Heart Association Scientist Development [0735308N]
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Disturbed blood flow induces inflammatory gene expression in endothelial cells, which promotes atherosclerosis. Flow stimulates the proinflammatory transcription factor nuclear factor (NF)-kappa B through integrin-and Rac-dependent production of reactive oxygen species (ROS). Previous work demonstrated that NF-kappa B activation by flow is matrix-specific, occurring in cells on fibronectin but not collagen. Activation of p21-activated kinase (PAK) followed the same matrix-dependent pattern. We now show that inhibiting PAK in cells on fibronectin blocked NF-kappa B activation by both laminar and oscillatory flow in vitro and at sites of disturbed flow in vivo. Constitutively active PAK rescued flow-induced NF-kappa B activation in cells on collagen. Surprisingly, PAK was not required for flow-induced ROS production. Instead, PAK modulated the ability of ROS to activate the NF-kappa B pathway. These data demonstrate that PAK controls NF-kappa B activation by modulating the sensitivity of cells to ROS.
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