title: Intrahepatic angiopoietin-2 correlates with chronic hepatitis C progression and is induced in hepatitis C virus replicon systems.
abstract: Chronic hepatitis C (CHC) is a major cause of cirrhosis and hepatocellular carcinoma and angiogenesis is closely related to the pathogenesis and progression of different chronic liver diseases (CLD). Thus, the intrahepatic expression of angiopoietins 1 and 2 (Ang1 and Ang2), as relevant mediators of pathological angiogenesis in several CLD, was investigated. In addition, the differential influence of structural and non-structural genomic regions of HCV on the expression of angiopoietins and the possible signalling involved were studied.
  
  
  
  Ang1 and Ang2 expression was evaluated by western blotting and enzyme-linked immunosorbent assay (ELISA) in liver homogenates of CHC patients (n=47) and uninfected subjects (n=8). Their association with disease progression (according to METAVIR classification) was assessed by Spearman's correlation. Statistical differences among the expression of angiopoietins at different CHC stages were calculated by Mann-Whitney U-test. Finally, the in vitro expression of Angiopoietins in HCV replicons (complete or non-structural subgenomic) and the main signalling pathways involved were also examined.
  
  
  
  Ang2 levels were significantly higher in the liver of CHC patients compared to controls and significantly correlated with inflammation and fibrosis. Accordingly, an increased expression of Ang2 was found in all HCV replicons tested. Interestingly, the inhibition of MEK and PI3K signalling pathways exerted differential effects on Ang2 expression concerning to the genomic region of HCV.
  
  
  
  Hepatitis C virus induces Ang2 expression in hepatocytes through different signalling routes which may lead to the disregulation of vascular homeostasis in the liver. Thus, pharmacologic intervention on Ang2 signalling might constitute an important therapeutic tool.
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Hernández-Bartolomé
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: López-Rodríguez
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.|CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: García-Buey
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
authors.forename: Samuel
authors.initials: S
authors.lastname: Martín-Vílchez
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Rodríguez-Muñoz
authors.affiliation: Molecular Biology Unit, Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Borque
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: González-Moreno
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Real-Martínez
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Mendoza-Ridruejo
authors.affiliation: Digestive Surgery Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Pérez
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.|CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Moreno-Otero
authors.affiliation: Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.|CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain.
authors.forename: Paloma
authors.identifier: 0000-0001-5308-2167
authors.initials: P
authors.lastname: Sanz-Cameno
mesh_terms: D000328:Adult; D000368:Aged; D042683:Angiopoietin-1 / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D018450:Disease Progression; D005260:Female; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012093:Replicon; D015398:Signal Transduction; D014764:Viral Proteins / Q000378:metabolism
chemical_list: C467630:ANGPT1 protein, human; C586513:ANGPT2 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D014764:Viral Proteins
keywords: 
  CHC
  ; HCV replicons; MEK; PI3K; angiopoietin-2; liver fibrosis