This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 103/6/671    most recent CIRCRESAHA.108.182097v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Orr, A. W. Articles by Schwartz, M. A. Search for Related Content PubMed PubMed Citation Articles by Orr, A. W. Articles by Schwartz, M. A. Related Collections Animal models of human disease Pathophysiology Cell biology/structural biology Cell signalling/signal transduction Gene expression Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors Related Article

(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

Related Article:

What Underlies Endothelial Shear Sensing? The Matrix, of Course

Lance S. Terada
Circ. Res. 2008 103: 562-564. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				C. Hahn, A. W. Orr, J. M. Sanders, K. A. Jhaveri, and M. A. Schwartz The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow Circ. Res., April 24, 2009; 104(8): 995 - 1003. [Abstract] [Full Text] [PDF]

				C. M. Mahoney, M. R. Morgan, A. Harrison, M. J. Humphries, and M. D. Bass Therapeutic Ultrasound Bypasses Canonical Syndecan-4 Signaling to Activate Rac1 J. Biol. Chem., March 27, 2009; 284(13): 8898 - 8909. [Abstract] [Full Text] [PDF]

				L. S. Terada What Underlies Endothelial Shear Sensing? The Matrix, of Course Circ. Res., September 12, 2008; 103(6): 562 - 564. [Full Text] [PDF]