title: Suppression of renin-angiotensin system attenuates hepatocarcinogenesis via angiogenesis inhibition in rats.
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.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Nara, Japan. yoshijih@naramed-u.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshii
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: Koji
authors.initials: K
authors.lastname: Yanase
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.forename: Masaharu
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Masahito
authors.initials: M
authors.lastname: Uemura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D004052:Diethylnitrosamine; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D020913:Perindopril / Q000494:pharmacology*; D011230:Precancerous Conditions / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002273:Carcinogens; D042461:Vascular Endothelial Growth Factor A; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D020913:Perindopril