title: Recruitment of the adaptor protein Nck to PECAM-1 couples oxidative stress to canonical NF-κB signaling and inflammation.
abstract: Oxidative stress stimulates nuclear factor κB (NF-κB) activation and NF-κB-dependent proinflammatory gene expression in endothelial cells during several pathological conditions, including ischemia/reperfusion injury. We found that the Nck family of adaptor proteins linked tyrosine kinase signaling to oxidative stress-induced activation of NF-κB through the classic IκB kinase-dependent pathway. Depletion of Nck prevented oxidative stress induced by exogenous hydrogen peroxide or hypoxia/reoxygenation injury from activating NF-κB in endothelial cells, increasing the abundance of the proinflammatory molecules ICAM-1 (intracellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) and recruiting leukocytes. Nck depletion also attenuated endothelial cell expression of genes encoding proinflammatory factors but not those encoding antioxidants. Nck promoted oxidative stress-induced activation of NF-κB by coupling the tyrosine phosphorylation of PECAM-1 (platelet endothelial cell adhesion molecule-1) to the activation of p21-activated kinase, which mediates oxidative stress-induced NF-κB signaling. Consistent with this mechanism, treatment of mice subjected to ischemia/reperfusion injury in the cremaster muscle with a Nck inhibitory peptide blocked leukocyte adhesion and emigration and the accompanying vascular leak. Together, these data identify Nck as an important mediator of oxidative stress-induced inflammation and a potential therapeutic target for ischemia/reperfusion injury.
authors.affiliation: Department of Pathology, Louisiana State University (LSU) Health Sciences Center Shreveport, Shreveport, LA 71130, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center Shreveport, Shreveport, LA 71130, USA.
authors.forename: Igor L
authors.initials: IL
authors.lastname: Leskov
authors.affiliation: Department Cell Biology and Anatomy, LSU Health Sciences Center Shreveport, Shreveport, LA 71130, USA.
authors.forename: Arif
authors.initials: A
authors.lastname: Yurdagul
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Thiel
authors.affiliation: Department of Pathology, Louisiana State University (LSU) Health Sciences Center Shreveport, Shreveport, LA 71130, USA. Department of Molecular and Cellular Physiology, LSU Health Sciences Center Shreveport, Shreveport, LA 71130, USA. Department Cell Biology and Anatomy, LSU Health Sciences Center Shreveport, Shreveport, LA 71130, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Kevil
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center Shreveport, Shreveport, LA 71130, USA.
authors.forename: Karen Y
authors.initials: KY
authors.lastname: Stokes
authors.affiliation: Department of Pathology, Louisiana State University (LSU) Health Sciences Center Shreveport, Shreveport, LA 71130, USA. Department Cell Biology and Anatomy, LSU Health Sciences Center Shreveport, Shreveport, LA 71130, USA. aorr@lsuhsc.edu.
authors.forename: A Wayne
authors.initials: AW
authors.lastname: Orr
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; C078332:Nck protein; D015513:Oncogene Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1