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(Circulation Research. 2008;103:671.)
© 2008 American Heart Association, Inc.

Integrative Physiology

p21-Activated Kinase Signaling Regulates Oxidant-Dependent NF-B Activation by Flow

A. Wayne Orr, Cornelia Hahn, Brett R. Blackman, Martin Alexander Schwartz

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.

Correspondence to Martin Alexander Schwartz, University of Virginia, Cardiovascular Research Center, 415 Lane Rd, Charlottesville, VA 22908. 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 • fluid shear stress • NF-B • reactive oxygen species

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