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01.04.2013 | Original Article—Liver, Pancreas, and Biliary Tract

Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis

verfasst von: Yosui Tamaki, Yukiomi Nakade, Taeko Yamauchi, Yuichi Makino, Shiro Yokohama, Mitsuyoshi Okada, Kazunobu Aso, Hiroyuki Kanamori, Tomohiko Ohashi, Ken Sato, Haruhisa Nakao, Masakazu Haneda, Masashi Yoneda

Erschienen in: Journal of Gastroenterology | Ausgabe 4/2013

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Abstract

Background

Angiotensin II type 1 receptor blockers (ARBs) have been reported to attenuate hepatic fibrosis in non-alcoholic steatohepatitis (NASH). However, it is uncertain whether ARBs prevent hepatocarcinogenesis in NASH even after hepatic fibrosis has developed.

Methods

Male Wistar rats were fed with a choline-deficient, l-amino acid-defined (CDAA) diet for 24 weeks, and then fed with the CDAA diet with telmisartan (2 mg/kg/day), a novel ARB, or vehicle for another 24 weeks. The liver histology and the expression of genes and proteins related to angiogenesis were investigated.

Results

The 24-week CDAA diet induced liver cirrhosis. The 48-week CDAA diet exacerbated liver cirrhosis, and developed hepatocellular carcinoma (HCC) in 54.6 % of the rats concurrently with increases of hypoxia-inducible factor-1α (HIF-1α) protein and vascular endothelial growth factor (VEGF) mRNA, which are potent angiogenic factors in the liver. Telmisartan inhibited hepatic fibrosis and preneoplastic lesions and prevented the development of HCC along with inducing decreases in HIF-1α protein and VEGF mRNA.

Conclusions

These data indicated that telmisartan may prevent hepatocarcinogenesis through the inhibition of hepatic angiogenesis even after liver cirrhosis has been established.

Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005;42:44–52.PubMedCrossRef

Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis. 2008;28:339–50.PubMedCrossRef

Shimada M, Hashimoto E, Taniai M, Hasegawa K, Okuda H, Hayashi N, et al. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol. 2002;37:154–60.PubMedCrossRef

Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology. 2008;135:111–21.PubMedCrossRef

Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst. 2000;92:1096–9.PubMedCrossRef

Pieruzzi F, Abassi ZA, Keiser HR. Expression of renin–angiotensin system components in the heart, kidneys, and lungs of rats with experimental heart failure. Circulation. 1995;92:3105–12.PubMedCrossRef

Kamezaki F, Tasaki H, Yamashita K, Shibata K, Hirakawa N, Tsutsui M, et al. Angiotensin receptor blocker improves coronary flow velocity reserve in hypertensive patients: comparison with calcium channel blocker. Hypertens Res. 2007;30:699–706.PubMedCrossRef

Stock P, Liefeldt L, Paul M, Ganten D. Local renin–angiotensin systems in cardiovascular tissues: localization and functional role. Cardiology. 1995;86(Suppl 1):2–8.PubMedCrossRef

Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001;34:745–50.PubMedCrossRef

10.

Bataller R, Sancho-Bru P, Gines P, Lora JM, Al-Garawi A, Sole M, et al. Activated human hepatic stellate cells express the renin–angiotensin system and synthesize angiotensin II. Gastroenterology. 2003;125:117–25.PubMedCrossRef

11.

Helmy A, Jalan R, Newby DE, Hayes PC, Webb DJ. Role of angiotensin II in regulation of basal and sympathetically stimulated vascular tone in early and advanced cirrhosis. Gastroenterology. 2000;118:565–72.PubMedCrossRef

12.

Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40:1222–5.PubMedCrossRef

13.

Yokohama S, Tokusashi Y, Nakamura K, Tamaki Y, Okamoto S, Okada M, et al. Inhibitory effect of angiotensin II receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis. World J Gastroenterol. 2006;12:322–6.PubMed

14.

Hirose A, Ono M, Saibara T, Nozaki Y, Masuda K, Yoshioka A, et al. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology. 2007;45:1375–81.PubMedCrossRef

15.

Jin H, Yamamoto N, Uchida K, Terai S, Sakaida I. Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet. Biochem Biophys Res Commun. 2007;364:801–7.PubMedCrossRef

16.

Yoshiji H, Kuriyama S, Noguchi R, Yoshii J, Ikenaka Y, Yanase K, et al. Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice. Gut. 2005;54:1768–75.PubMedCrossRef

17.

Liu Y, Poon RT, Li Q, Kok TW, Lau C, Fan ST. Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res. 2005;65:3691–9.PubMedCrossRef

18.

Yoshiji H, Kuriyama S, Noguchi R, Ikenaka Y, Kitade M, Kaji K, et al. Angiotensin-II and vascular endothelial growth factor interaction plays an important role in rat liver fibrosis development. Hepatol Res. 2006;36:124–9.PubMedCrossRef

19.

Ghoshal AK, Farber E. The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens. Carcinogenesis. 1984;5:1367–70.PubMedCrossRef

20.

Squire RA, Levitt MH. Report of a workshop on classification of specific hepatocellular lesions in rats. Cancer Res. 1975;35:3214–23.PubMed

21.

Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis. 2001;21:3–16.PubMedCrossRef

22.

Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–8.PubMedCrossRef

23.

Morgan TR, Mandayam S, Jamal MM, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004;127:S87–96.PubMedCrossRef

24.

Nguyen VT, Law MG, Dore GJ. Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden. J Viral Hepat. 2009;16:453–63.PubMedCrossRef

25.

Sakaida I, Matsumura Y, Kubota M, Kayano K, Takenaka K, Okita K. The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells, reducing procollagen gene expression in rat liver fibrosis induced by choline-deficient l-amino acid-defined diet. Hepatology. 1996;23:755–63.PubMed

26.

Ghoshal AK, Ahluwalia M, Farber E. The rapid induction of liver cell death in rats fed a choline-deficient methionine-low diet. Am J Pathol. 1983;113:309–14.PubMed

27.

Yao ZM, Vance DE. The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. J Biol Chem. 1988;263:2998–3004.PubMed

28.

Nakae D, Yoshiji H, Maruyama H, Kinugasa T, Denda A, Konishi Y. Production of both 8-hydroxydeoxyguanosine in liver DNA and gamma-glutamyltransferase-positive hepatocellular lesions in rats given a choline-deficient, l-amino acid-defined diet. Jpn J Cancer Res. 1990;81:1081–4.PubMedCrossRef

29.

Nakae D. Endogenous liver carcinogenesis in the rat. Pathol Int. 1999;49:1028–42.PubMedCrossRef

30.

Yamamoto H, Kondo M, Nakamori S, Nagano H, Wakasa K, Sugita Y, et al. JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis1. Gastroenterology. 2003;125:556–71.PubMedCrossRef

31.

Seki S, Kitada T, Yamada T, Sakaguchi H, Nakatani K, Wakasa K. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol. 2002;37:56–62.PubMedCrossRef

32.

Fox ES, Brower JS, Bellezzo JM, Leingang KA. N-acetylcysteine and alpha-tocopherol reverse the inflammatory response in activated rat Kupffer cells. J Immunol. 1997;158:5418–23.PubMed

33.

Goossens V, Grooten J, De Vos K, Fiers W. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci USA. 1995;92:8115–9.PubMedCrossRef

34.

Bataller R, Gabele E, Parsons CJ, Morris T, Yang L, Schoonhoven R, et al. Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats. Hepatology. 2005;41:1046–55.PubMedCrossRef

35.

Grotendorst GR. Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev. 1997;8:171–9.PubMedCrossRef

36.

Paradis V, Dargere D, Bonvoust F, Vidaud M, Segarini P, Bedossa P. Effects and regulation of connective tissue growth factor on hepatic stellate cells. Lab Invest. 2002;82:767–74.PubMed

37.

Schutte K, Bornschein J, Malfertheiner P. Hepatocellular carcinoma—epidemiological trends and risk factors. Dig Dis. 2009;27:80–92.PubMed

38.

Sakaida I, Hironaka K, Uchida K, Suzuki C, Kayano K, Okita K. Fibrosis accelerates the development of enzyme-altered lesions in the rat liver. Hepatology. 1998;28:1247–52.PubMedCrossRef

39.

Kerbel RS. Tumor angiogenesis: past, present and the near future. Carcinogenesis. 2000;21:505–15.PubMedCrossRef

40.

Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science. 1999;284:808–12.PubMedCrossRef

41.

Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology. 2005;69(Suppl 3):4–10.PubMedCrossRef

42.

Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, et al. Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice. Hepatology. 2001;39:1517–24.CrossRef

43.

Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.PubMedCrossRef

44.

Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 2000;19:4298–309.PubMedCrossRef

45.

Onori P, Morini S, Franchitto A, Sferra R, Alvaro D, Gaudio E. Hepatic microvascular features in experimental cirrhosis: a structural and morphometrical study in CCl4-treated rats. J Hepatol. 2000;33:555–63.PubMedCrossRef

46.

Wang YQ, Luk JM, Ikeda K, Man K, Chu AC, Kaneda K, et al. Regulatory role of vHL/HIF-1alpha in hypoxia-induced VEGF production in hepatic stellate cells. Biochem Biophys Res Commun. 2004;317:358–62.PubMedCrossRef

47.

Semenza GL. Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today. 2007;12:853–9.PubMedCrossRef

48.

Nakamura K, Zen Y, Sato Y, Kozaka K, Matsui O, Harada K, et al. Vascular endothelial growth factor, its receptor Flk-1, and hypoxia inducible factor-1alpha are involved in malignant transformation in dysplastic nodules of the liver. Hum Pathol. 2007;38:1532–46.PubMedCrossRef

49.

Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA. 1997;94:8104–9.PubMedCrossRef

50.

Fujita K, Yoneda M, Wada K, Mawatari H, Takahashi H, Kirikoshi H, et al. Telmisartan, an angiotensin II type 1 receptor blocker, controls progress of nonalcoholic steatohepatitis in rats. Dig Dis Sci. 2007;52:3455–64.PubMedCrossRef

51.

Schupp M, Janke J, Clasen R, Unger T, Kintscher U. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation. 2004;109:2054–7.PubMedCrossRef

52.

Sugimoto K, Kazdova L, Qi NR, Hyakukoku M, Kren V, Simakova M, et al. Telmisartan increases fatty acid oxidation in skeletal muscle through a peroxisome proliferator-activated receptor-gamma dependent pathway. J Hypertens. 2008;26:1209–15.PubMedCrossRef

53.

Moreno M, Ramalho LN, Sancho-Bru P, Ruiz-Ortega M, Ramalho F, Abraldes JG, et al. Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver. Am J Physiol Gastrointest Liver Physiol. 2009;296:G147–56.PubMedCrossRef

54.

Bartoli M, Al-Shabrawey M, Labazi M, Behzadian MA, Istanboli M, El-Remessy AB, et al. HMG-CoA reductase inhibitors (statin) prevents retinal neovascularization in a model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci. 2009;50:4934–40.PubMedCrossRef

55.

Xu K, Ding Q, Fang Z, Zheng J, Gao P, Lu Y, et al. Silencing of HIF-1alpha suppresses tumorigenicity of renal cell carcinoma through induction of apoptosis. Cancer Gene Ther. 2010;17:212–22.PubMedCrossRef

56.

Kaji K, Yoshiji H, Kitade M, Ikenaka Y, Noguchi R, Shirai Y, et al. Combination treatment of angiotensin II type I receptor blocker and new oral iron chelator attenuates progression of nonalcoholic steatohepatitis in rats. Am J Physiol Gastrointest Liver Physiol. 2011;300:G1094–104.PubMedCrossRef

57.

Kudo H, Yata Y, Takahara T, Kawai K, Nakayama Y, Kanayama M, et al. Telmisartan attenuates progression of steatohepatitis in mice: role of hepatic macrophage infiltration and effects on adipose tissue. Liver Int. 2009;29:988–96.PubMedCrossRef

58.

Sanchez-Lopez E, Lopez AF, Esteban V, Yague S, Egido J, Ruiz-Ortega M, et al. Angiotensin II regulates vascular endothelial growth factor via hypoxia-inducible factor-1alpha induction and redox mechanisms in the kidney. Antioxid Redox Signal. 2005;7:1275–84.PubMedCrossRef

Titel: Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis
verfasst von: Yosui Tamaki
Yukiomi Nakade
Taeko Yamauchi
Yuichi Makino
Shiro Yokohama
Mitsuyoshi Okada
Kazunobu Aso
Hiroyuki Kanamori
Tomohiko Ohashi
Ken Sato
Haruhisa Nakao
Masakazu Haneda
Masashi Yoneda
Publikationsdatum: 01.04.2013
Verlag: Springer Japan
Erschienen in: Journal of Gastroenterology / Ausgabe 4/2013
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-012-0651-7

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