title: Altered nitric oxide production mediates matrix-specific PAK2 and NF-κB activation by flow.
abstract: Shear stress generated by distinct blood flow patterns modulates endothelial cell phenotype to spatially restrict atherosclerotic plaque development. Signaling through p21-activated kinase (PAK) mediates several of the deleterious effects of shear stress, including enhanced NF-κB activation and proinflammatory gene expression. Whereas shear stress activates PAK in endothelial cells on a fibronectin matrix, basement membrane proteins limit shear-induced PAK activation and inflammation through a protein kinase A-dependent pathway; however, the mechanisms underlying this regulation were unknown. We show that basement membrane proteins limit membrane recruitment of PAK2, the dominant isoform in endothelial cells, by blocking its interaction with the adaptor protein Nck. This uncoupling response requires protein kinase A-dependent nitric oxide production and subsequent PAK2 phosphorylation on Ser-20 in the Nck-binding domain. Of importance, shear stress does not stimulate nitric oxide production in endothelial cells on fibronectin, resulting in enhanced PAK activation, NF-κB phosphorylation, ICAM-1 expression, and monocyte adhesion. These data demonstrate that differential flow-induced nitric oxide production regulates matrix-specific PAK signaling and describe a novel mechanism of nitric oxide-dependent NF-κB inhibition.
authors.affiliation: Department of Pathology, LSU Health Sciences Center, Shreveport, LA 71103, USA.
authors.forename: Arif
authors.initials: A
authors.lastname: Yurdagul
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Steven Daniel
authors.initials: SD
authors.lastname: Funk
authors.forename: Patrick
authors.initials: P
authors.lastname: Albert
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Kevil
authors.forename: A Wayne
authors.initials: AW
authors.lastname: Orr
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D001485:Basement Membrane / Q000378:metabolism; D001696:Biomechanical Phenomena; D002417:Cattle; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D013312:Stress, Physiological; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; D009569:Nitric Oxide; D054462:p21-Activated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases