title: Fn14 is upregulated in cytokine-stimulated vascular smooth muscle cells and is expressed in human carotid atherosclerotic plaques: modulation by atorvastatin.
abstract: OBJECTIVE
  Interaction between different members of the tumor necrosis factor superfamily and their receptors elicits diverse biologic actions that are implicated in the pathogenesis of atherosclerosis. We have analyzed the expression of Fn14 and its ligand TWEAK in carotid atherosclerotic plaques and its potential modulation by atorvastatin in vivo. Furthermore, we have studied whether proinflammatory cytokines regulate Fn14 expression in human aortic smooth muscle cells (hASMCs) in culture as well as the potential regulation by atorvastatin treatment.
  
  
  METHODS
  Fn14 and TWEAK expression was analyzed in human carotid atherosclerotic plaques. Furthermore, Fn14 expression was studied in hASMCs in culture.
  
  
  RESULTS
  Fn14 and TWEAK are expressed in macrophages and smooth muscle cells in carotid atherosclerotic plaques. Proinflammatory cytokines (interleukin-1beta and interferon-gamma) upregulate Fn14 expression in hASMCs. This effect was prevented by atorvastatin treatment and reversed by mevalonate and geranylgeranyl pyrophosphate. Geranylgeranyl transferase inhibitor, toxin B (Rac and Rho inhibitor), C3 exoenzyme (Rho inhibitor), and Y-27632 (Rho kinase inhibitor) also decreased Fn14 expression, implicating the Rho/Rho kinase pathway in the regulation of Fn14 expression. Finally, atorvastatin treatment reduced Fn14 expression in vivo.
  
  
  CONCLUSIONS
  TWEAK and Fn14 are expressed in atherosclerotic plaques and could be novel mediators of atherosclerosis. Atorvastatin diminishes Fn14 expression in vitro and in vivo providing novel information of the beneficial properties of statins.
authors.affiliation: Vascular Research Laboratory, Fundación Jiménez Díaz, Autonoma University, Avenida Reyes Católicos 2, 28040, Madrid, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Muñoz-García
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Martín-Ventura
authors.forename: Elena
authors.initials: E
authors.lastname: Martínez
authors.forename: Santiago
authors.initials: S
authors.lastname: Sánchez
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Hernández
authors.forename: Luis
authors.initials: L
authors.lastname: Ortega
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
mesh_terms: D000368:Aged; D001011:Aorta / Q000166:cytology; D000069059:Atorvastatin; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D000074049:Cytokine TWEAK; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D006538:Heptanoic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000494:pharmacology; D002537:Intracranial Arteriosclerosis / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D000074049:Cytokine TWEAK; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; D000069059:Atorvastatin; D020741:rho GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid