title: Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) and nuclear factor-κB (NF-κB): a feed-forward loop for systemic and vascular inflammation.
abstract: The interaction between vascular cells and macrophages is critical during vascular remodeling. Here we report that the scaffolding protein, ezrin-binding phosphoprotein 50 (EBP50), is a central regulator of macrophage and vascular smooth muscle cells (VSMC) function. EBP50 is up-regulated in intimal VSMC following endoluminal injury and promotes neointima formation. However, the mechanisms underlying these effects are not fully understood. Because of the fundamental role that inflammation plays in vascular diseases, we hypothesized that EBP50 mediates macrophage activation and the response of vessels to inflammation. Indeed, EBP50 expression increased in primary macrophages and VSMC, and in the aorta of mice, upon treatment with LPS or TNFα. This increase was nuclear factor-κB (NF-κB)-dependent. Conversely, activation of NF-κB was impaired in EBP50-null VSMC and macrophages. We found that inflammatory stimuli promote the formation of an EBP50-PKCζ complex at the cell membrane that induces NF-κB signaling. Macrophage activation and vascular inflammation after acute LPS treatment were reduced in EBP50-null cells and mice as compared with WT. Furthermore, macrophage recruitment to vascular lesions was significantly reduced in EBP50 knock-out mice. Thus, EBP50 and NF-κB participate in a feed-forward loop leading to increased macrophage activation and enhanced response of vascular cells to inflammation.
authors.affiliation: From the Department of Pharmacology and Chemical Biology.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Leslie
authors.forename: Gyun Jee
authors.initials: GJ
authors.lastname: Song
authors.forename: Stacey
authors.initials: S
authors.lastname: Barrick
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Wehbi
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vilardaga
authors.forename: Philip M
authors.initials: PM
authors.lastname: Bauer
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bisello
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D025461:Feedback, Physiological; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014657:Vasculitis / Q000209:etiology / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D010750:Phosphoproteins; D011493:Protein Kinase C; D017923:Sodium-Hydrogen Exchangers; D014409:Tumor Necrosis Factor-alpha; D000099221:Protein Kinase C zeta; C093376:sodium-hydrogen exchanger regulatory factor
keywords: EBP50; Inflammation; Macrophages; NF-Kappa B (NF-KB); NHERF1; PDZ Domain; PKC Zeta; Scaffold Proteins; Vascular Biology; Vascular Smooth Muscle Cells