title: Inhibition of tyrosine kinase receptor Tie2 reverts HCV-induced hepatic stellate cell activation.
abstract: BACKGROUND
  Hepatitis C virus (HCV) infection is a major cause of chronic liver disease (CLD) and is frequently linked to intrahepatic microvascular disorders. Activation of hepatic stellate cells (HSC) is a central event in liver damage, due to their contribution to hepatic renewal and to the development of fibrosis and hepatocarcinoma. During the progression of CLDs, HSC attempt to restore injured tissue by stimulating repair processes, such as fibrosis and angiogenesis. Because HSC express the key vascular receptor Tie2, among other angiogenic receptors and mediators, we analyzed its involvement in the development of CLD.
  
  
  METHODS
  Tie2 expression was monitored in HSC cultures that were exposed to media from HCV-expressing cells (replicons). The effects of Tie2 blockade on HSC activation by either neutralizing antibody or specific signaling inhibitors were also examined.
  
  
  RESULTS
  Media from HCV-replicons enhanced HSC activation and invasion and upregulated Tie2 expression. Notably, the blockade of Tie2 receptor (by a specific neutralizing antibody) or signaling (by selective AKT and MAPK inhibitors) significantly reduced alpha-smooth muscle actin (α-SMA) expression and the invasive potential of HCV-conditioned HSC.
  
  
  CONCLUSIONS
  These findings ascribe a novel profibrogenic function to Tie2 receptor in the progression of chronic hepatitis C, highlighting the significance of its dysregulation in the evolution of CLDs and its potential as a novel therapeutic target.
authors.affiliation: Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.
authors.forename: Samuel
authors.initials: S
authors.lastname: Martín-Vílchez
authors.affiliation: Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Rodríguez-Muñoz
authors.affiliation: Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: López-Rodríguez
authors.affiliation: Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.
authors.lastname: Hernández-Bartolomé
authors.affiliation: Unidad de Biología Molecular, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Borque-Iñurrita
authors.affiliation: Unidad de Biología Molecular, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Molina-Jiménez
authors.affiliation: Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: García-Buey
authors.affiliation: Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Moreno-Otero
authors.affiliation: Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Sanz-Cameno
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D016174:Hepacivirus / Q000502:physiology*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D042787:Receptor, TIE-2 / Q000032:analysis / Q000037:antagonists & inhibitors*
chemical_list: D057134:Antibodies, Neutralizing; D047428:Protein Kinase Inhibitors; D042787:Receptor, TIE-2