title: Peptide inhibitor of NF-κB translocation ameliorates experimental atherosclerosis.
abstract: Atherosclerosis is a chronic inflammatory disease of the arterial wall. NF-κB is a major regulator of inflammation that controls the expression of many genes involved in atherogenesis. Activated NF-κB was detected in human atherosclerotic plaques, and modulation of NF-κB inflammatory activity limits disease progression in mice. Herein, we investigate the anti-inflammatory and atheroprotective effects of a cell-permeable peptide containing the NF-κB nuclear localization sequence (NLS). In vascular smooth muscle cells and macrophages, NLS peptide specifically blocked the importin α-mediated nuclear import of NF-κB and prevented lipopolysaccharide-induced pro-inflammatory gene expression, cell migration, and oxidative stress. In experimental atherosclerosis (apolipoprotein E-knockout mice fed a high-fat diet), i.p., 0.13 μmol/day NLS peptide administration for 5 weeks attenuated NF-κB activation in atherosclerotic plaques. NLS peptide significantly inhibited lesion development at both early (age 10 weeks) and advanced (age 28 weeks) stages of atherosclerosis in mice, without affecting serum lipid levels. Plaques from NLS-treated mice contained fewer macrophages of pro-inflammatory M1 subtype than those from respective untreated controls. By contrast, the relative smooth muscle cell and collagen content was increased, indicating a more stable plaque phenotype. NLS peptide also attenuated pro-inflammatory gene expression and oxidative stress in aortic lesions. Our study demonstrates that targeting NF-κB nuclear translocation hampers inflammation and atherosclerosis development and identifies cell-permeable NLS peptide as a potential anti-atherosclerotic agent.
authors.affiliation: Renal and Vascular Inflammation Laboratory, Department of Nephrology, IIS-Fundación Jiménez Díaz, Autonoma University, Madrid, Spain.
authors.forename: Beñat
authors.initials: B
authors.lastname: Mallavia
authors.forename: Carlota
authors.initials: C
authors.lastname: Recio
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Oguiza
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Ortiz-Muñoz
authors.forename: Iolanda
authors.initials: I
authors.lastname: Lazaro
authors.forename: Virginia
authors.initials: V
authors.lastname: Lopez-Parra
authors.forename: Oscar
authors.initials: O
authors.lastname: Lopez-Franco
authors.forename: Susann
authors.initials: S
authors.lastname: Schindler
authors.forename: Reinhard
authors.initials: R
authors.lastname: Depping
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez-Guerrero
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D058226:Plaque, Atherosclerotic; D021381:Protein Transport / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D028884:Karyopherins; D016328:NF-kappa B; D019913:Nuclear Localization Signals; D010455:Peptides