Abstract
Recent studies have shown that the renin-angiotensin system (RAS) as well as angiogenesis is involved in tumor development. The aim of the present study was to examine the interaction of RAS, angiogenesis and a potent angiogenic factor, namely the vascular endothelial growth factor (VEGF), in the hepatocarcinogenesis process. In a diethylnitrosamine-induced rat hepatocarcinogenesis model, a clinically used angiotensin-converting enzyme inhibitor, perindopril (PE), significantly suppressed glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions along with inhibition of neovascularization in the liver. The hepatic expression of VEGF was also attenuated. The degree of angiogenesis correlated well with the development of preneoplastic lesions. Our in vitro study showed that PE significantly suppressed VEGF-induced tubular formation and the migration of endothelial cells (EC), whereas it did not affect the proliferation of EC. These results suggested that RAS plays an important role in hepatocarcinogenesis, at least partly through VEGF-mediated angiogenesis.
MeSH terms
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Angiotensin-Converting Enzyme Inhibitors / pharmacology*
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Animals
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Carcinogens
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Cell Growth Processes / drug effects
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Cell Growth Processes / physiology
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Diethylnitrosamine
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Glutathione Transferase / antagonists & inhibitors
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Glutathione Transferase / biosynthesis
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Liver / blood supply
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Liver / drug effects
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Liver / enzymology
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Liver Neoplasms, Experimental / blood supply*
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Liver Neoplasms, Experimental / chemically induced
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Liver Neoplasms, Experimental / enzymology
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Liver Neoplasms, Experimental / prevention & control*
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Male
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / enzymology
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Neovascularization, Pathologic / pathology
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Neovascularization, Pathologic / prevention & control
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Perindopril / pharmacology*
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Precancerous Conditions / drug therapy
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Precancerous Conditions / enzymology
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Precancerous Conditions / pathology
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Rats
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Rats, Inbred F344
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Renin-Angiotensin System / drug effects*
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Renin-Angiotensin System / physiology*
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Vascular Endothelial Growth Factor A / biosynthesis
Substances
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Angiotensin-Converting Enzyme Inhibitors
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Carcinogens
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Vascular Endothelial Growth Factor A
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Diethylnitrosamine
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Glutathione Transferase
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Perindopril