Angiotensin-I-converting enzyme inhibitors may be an alternative anti-angiogenic strategy in the treatment of liver fibrosis and hepatocellular carcinoma. Possible role of vascular endothelial growth factor

Tumour Biol. Nov-Dec 2002;23(6):348-56. doi: 10.1159/000069792.

Abstract

The renin-angiotensin system (RAS) is frequently activated in patients with chronic liver diseases. Angiotensin-II (AT-II), which is produced by angiotensin-converting enzyme (ACE), has many physiological effects, including strong pro-angiogenic activity. AT-II induces the potent angiogenic factor, vascular endothelial growth factor (VEGF). Recent studies have revealed that angiogenesis is an essential process in many pathological events, such as tumor growth including hepatocellular carcinoma (HCC), and even in liver fibrogenesis. ACE inhibitors are currently widely used as anti-hypertensive agents in clinical practice. Studies have found that the ACE inhibitor, perindopril (PE), which is a potent inhibitor of experimental HCC growth and angiogenesis, is associated with the suppression of VEGF at a clinically comparable dose. PE also markedly suppressed the hepatocarcinogenesis step. In liver fibrogenesis, AT-II is known to stimulate proliferation and production of tissue inhibitor of metalloproteinases-1 (TIMP-1) in activated hepatic stellate cells (Ac-HSC), which play a pivotal role in liver fibrosis development. PE markedly inhibited liver fibrogenesis associated with suppression of Ac-HSC proliferation and TIMP-1 expression via protein kinase-C, which serves as an intracellular signaling pathway. Since ACE inhibitor is used widely in clinical practice without serious side effects, it may provide an alternative new strategy for the treatment of liver fibrosis and HCC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Angiotensin II / physiology
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / prevention & control
  • Endothelial Growth Factors / biosynthesis
  • Endothelial Growth Factors / genetics
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis, Experimental / drug therapy
  • Liver Cirrhosis, Experimental / pathology
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / etiology
  • Liver Neoplasms / prevention & control
  • Liver Neoplasms, Experimental / blood supply
  • Liver Neoplasms, Experimental / drug therapy
  • Liver Neoplasms, Experimental / prevention & control
  • Lymphokines / biosynthesis
  • Lymphokines / genetics
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Physiologic / physiology
  • Perindopril / therapeutic use
  • Renin-Angiotensin System / drug effects
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1 / biosynthesis
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / immunology
  • Vascular Endothelial Growth Factor Receptor-2 / biosynthesis
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / immunology
  • Vascular Endothelial Growth Factors

Substances

  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Antibodies, Monoclonal
  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Neoplasm Proteins
  • Tissue Inhibitor of Metalloproteinase-1
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Angiotensin II
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-2
  • Perindopril