Published online before print July 31, 2008, doi: 10.1161/CIRCRESAHA.108.182097
Submitted on March 17, 2008
Revised on July 22, 2008
Accepted on July 23, 2008
p21-Activated Kinase Signaling Regulates Oxidant-Dependent Nuclear Factor 
B Activation by Flow
A. Wayne Orr ;
From the Robert M. Berne Cardiovascular Research Center (A.W.O., C.H., B.R.B., M.A.S.), Departments of Microbiology (A.W.O., M.A.S.), and Biomedical Engineering (B.R.B.), Mellon Prostate Cancer Research Center (M.A.S.), University of Virginia, Charlottesville; and Department of Pathology (A.W.O.), Louisiana State University Health Sciences Center, Shreveport, La.
* To whom correspondence should be addressed. E-mail: maschwartz{at}virginia.edu.
Disturbed blood flow induces inflammatory gene expression in endothelial cells, which promotes atherosclerosis. Flow stimulates the proinflammatory transcription factor nuclear factor (NF)-
B through integrin- and Rac-dependent production of reactive oxygen species (ROS). Previous work demonstrated that NF-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-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-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-B pathway. These data demonstrate that PAK controls NF-B activation by modulating the sensitivity of cells to ROS.
Key words: endothelial cell dysfunction • extracellular matrix • flow shear stress • NF-
B •
reactive oxygen species