Suppression of renin-angiotensin system attenuates hepatocarcinogenesis via angiogenesis inhibition in rats.
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.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Nara, Japan. yoshijih@naramed-u.ac.jp
Noguchi
Ryuichi
R
Kuriyama
Shigeki
S
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Yanase
Koji
K
Namisaki
Tadashi
T
Kitade
Mitsuteru
M
Yamazaki
Masaharu
M
Uemura
Masahito
M
Fukui
Hiroshi
H
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
D000806:Angiotensin-Converting Enzyme Inhibitors; D002273:Carcinogens; D042461:Vascular Endothelial Growth Factor A; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D020913:Perindopril