title: Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression.
abstract: Oxidized low-density lipoprotein (oxLDL) accumulates early in atherosclerosis and promotes endothelial nuclear factor κB (NF-κB) activation, proinflammatory gene expression and monocyte adhesion. Like for other atherogenic factors, oxLDL-induced proinflammatory responses requires integrin-dependent focal adhesion kinase (FAK, also known as PTK2) signaling; however, the mechanism by which FAK mediates oxLDL-dependent NF-κB signaling has yet to be revealed. We now show that oxLDL induces NF-κB activation and VCAM-1 expression through FAK-dependent IκB kinase β (IKKβ, also known as IKBKB) activation. We further identify FAK-dependent activation of p90 ribosomal S6 kinase family proteins (RSK) as a crucial mediator of oxLDL-dependent IKKβ and NF-κB signaling, as inhibiting RSK blocks oxLDL-induced IKKβ and NF-κB activation, VCAM-1 expression and monocyte adhesion. Finally, transgenic mice containing a kinase-dead mutation in FAK specifically in the endothelial cells show reduced RSK activity, decreased VCAM-1 expression and reduced macrophage accumulation in regions of early atherosclerosis. Taken together, our data elucidates a new mechanism whereby oxLDL-induced endothelial FAK signaling drives an ERK-RSK pathway to activate IKKβ and NF-κB signaling and proinflammatory gene expression.
authors.affiliation: Department of Pathology and Translational Pathobiology, LSU Health Sciences Center, Shreveport, LA 71130, USA Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Arif
authors.initials: A
authors.lastname: Yurdagul
authors.affiliation: UCSD San Diego, Moores Cancer Center, Department of Reproductive Medicine, 0803 3855 Health Sciences Dr., La Jolla, CA 92093, USA.
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Sulzmaier
authors.affiliation: UCSD San Diego, Moores Cancer Center, Department of Reproductive Medicine, 0803 3855 Health Sciences Dr., La Jolla, CA 92093, USA State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Xiao L
authors.initials: XL
authors.lastname: Chen
authors.affiliation: Department of Cellular and Molecular Physiology, LSU Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Pattillo
authors.affiliation: UCSD San Diego, Moores Cancer Center, Department of Reproductive Medicine, 0803 3855 Health Sciences Dr., La Jolla, CA 92093, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Schlaepfer
authors.affiliation: Department of Pathology and Translational Pathobiology, LSU Health Sciences Center, Shreveport, LA 71130, USA Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, LA 71130, USA aorr@lsuhsc.edu.
authors.forename: A Wayne
authors.initials: AW
authors.lastname: Orr
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002448:Cell Adhesion; D042783:Endothelial Cells / Q000502:physiology*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008077:Lipoproteins, LDL; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D051550:I-kappa B Kinase
keywords: Atherosclerosis; FAK; Focal adhesion kinase; NF-κB; Nuclear factor κB; OxLDL; Oxidized LDL; RSK; Ribosomal S6 kinase