title: Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition.
abstract: OBJECTIVE
  Studies in experimental models of cirrhosis showed that anti-angiogenic treatments may be effective for the treatment of liver fibrosis. In this context, angiopoietins are potential therapeutic targets as they are involved in the maintenance and stabilization of newly formed blood vessels. In addition, angiopoietin-2 is expressed in fibrotic livers and its inhibition in tumours results in vessel stability. Therefore, our study was aimed to assess the therapeutic utility of inhibiting angiopoietin-2.
  
  
  METHODS
  Circulating levels of angiopoietin-1 and angiopoietin-2 were quantified by ELISA in CCl4 -treated rats and in patients with cirrhosis. In vivo blockade of angiopoietin-2 in rats with liver fibrosis was performed with a chemically programmed antibody, CVX-060.
  
  
  RESULTS
  High levels of angiopoietin-2 were found in the systemic and suprahepatic circulation of cirrhotic patients and the ratio angiopoietin-1/angiopoietin-2 inversely correlated with prognostic models for alcoholic liver disease. Chronic treatment of CCl4 -treated rats with CVX-060 was associated with a significant decrease in inflammatory infiltrate, normalization of the hepatic microvasculature and reduction in VCAM-1 vascular expression. The anti-angiopoietin-2 treatment was also associated with less liver fibrosis and with lower levels of circulating transaminases. CVX-060 treatment was not associated with either vascular pruning in healthy tissue or compensatory overexpression of VEGF.
  
  
  CONCLUSIONS
  Inhibition of angiopoietin-2 is an effective and safe treatment for liver fibrosis in CCl4 -treated rats, acting mainly through the induction of vessel normalization and the attenuation of hepatic inflammatory infiltrate. Therefore, inhibition of angiopoietin-2 offers a therapeutic alternative for liver fibrosis.
authors.affiliation: Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Pauta
authors.forename: Jordi
authors.initials: J
authors.lastname: Ribera
authors.forename: Pedro
authors.initials: P
authors.lastname: Melgar-Lesmes
authors.forename: Gregori
authors.initials: G
authors.lastname: Casals
authors.forename: Juan
authors.initials: J
authors.lastname: Rodríguez-Vita
authors.forename: Vedrana
authors.initials: V
authors.lastname: Reichenbach
authors.forename: Guillermo
authors.initials: G
authors.lastname: Fernandez-Varo
authors.forename: Blai
authors.initials: B
authors.lastname: Morales-Romero
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
authors.forename: Javier
authors.initials: J
authors.lastname: Michelena
authors.forename: Jose
authors.initials: J
authors.lastname: Altamirano
authors.forename: Wladimiro
authors.initials: W
authors.lastname: Jiménez
authors.forename: Manuel
authors.initials: M
authors.lastname: Morales-Ruiz
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006519:Hepatitis, Alcoholic / Q000097:blood*; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000097:blood*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017208:Rats, Wistar; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C586513:ANGPT2 protein, human; D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D015415:Biomarkers; D018796:Immunoconjugates; D018836:Inflammation Mediators; D019010:Vascular Cell Adhesion Molecule-1; D042787:Receptor, TIE-2
keywords: CVX-060; angiopoietins; chronic liver disease; liver sinusoidal endothelial cells; portal hypertension