p21-Activated Kinase Signaling Regulates Oxidant-Dependent NF- B Activation by Flow
نویسندگان
چکیده
Disturbed blood flow induces inflammatory gene expression in endothelial cells, which promotes atherosclerosis. Flow stimulates the proinflammatory transcription factor nuclear factor (NF)B through integrinand Rac-dependent production of reactive oxygen species (ROS). Previous work demonstrated that NFB 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 NFB activation by both laminar and oscillatory flow in vitro and at sites of disturbed flow in vivo. Constitutively active PAK rescued flow-induced NFB 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 NFB pathway. These data demonstrate that PAK controls NFB activation by modulating the sensitivity of cells to ROS. (Circ Res. 2008;103:671-679.)
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