p21-activated kinase signaling regulates oxidant-dependent NF-kappa B activation by flow.
Disturbed blood flow induces inflammatory gene expression in endothelial cells, which promotes atherosclerosis. Flow stimulates the proinflammatory transcription factor nuclear factor (NF)-kappaB through integrin- and Rac-dependent production of reactive oxygen species (ROS). Previous work demonstrated that NF-kappaB 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-kappaB activation by both laminar and oscillatory flow in vitro and at sites of disturbed flow in vivo. Constitutively active PAK rescued flow-induced NF-kappaB 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-kappaB pathway. These data demonstrate that PAK controls NF-kappaB activation by modulating the sensitivity of cells to ROS.
Orr
A Wayne
AW
Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Hahn
Cornelia
C
Blackman
Brett R
BR
Schwartz
Martin Alexander
MA
D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology; D002417:Cattle; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D016877:Oxidants / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D033081:Shear Strength; D015398:Signal Transduction / Q000502:physiology*; D054462:p21-Activated Kinases / Q000502:physiology*
D016328:NF-kappa B; D016877:Oxidants; D017382:Reactive Oxygen Species; D054462:p21-Activated Kinases