Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition

Authors

  • Montse Pauta,

    1. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
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    • These authors shared first authorship
  • Jordi Ribera,

    1. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
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    • These authors shared first authorship
  • Pedro Melgar-Lesmes,

    1. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
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  • Gregori Casals,

    1. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
    2. Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain
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  • Juan Rodríguez-Vita,

    1. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
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  • Vedrana Reichenbach,

    1. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
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  • Guillermo Fernandez-Varo,

    1. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
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  • Blai Morales-Romero,

    1. Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain
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  • Ramon Bataller,

    1. Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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  • Javier Michelena,

    1. Liver Unit-Institut de Malalties Digestives, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
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  • Jose Altamirano,

    1. Liver Unit-Institut de Malalties Digestives, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
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  • Wladimiro Jiménez,

    1. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
    2. Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain
    3. Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain
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  • Manuel Morales-Ruiz

    1. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
    2. Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain
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Correspondence

Manuel Morales-Ruiz, PhD, Department of Biochemistry and Molecular Genetics, Hospital Clinic of Barcelona, 170 Villarroel Street, Barcelona 08036, Spain

Tel: +34 9 3227 5466

Fax: +34 9 3227 5697

e-mail: morales@clinic.ub.es

Abstract

Background & Aims

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.

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