Journal of Hepatology
Volume 51, Issue 5 , Pages 865-873 , November 2009

Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats

  • Thomas Reiberger

      Affiliations

    • Department of Gastroenterology and Hepatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
    • ,
  • Bernhard Angermayr

      Affiliations

    • Department of Gastroenterology and Hepatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
    • ,
  • Philipp Schwabl

      Affiliations

    • Department of Gastroenterology and Hepatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
    • ,
  • Natascha Rohr-Udilova

      Affiliations

    • Department of Gastroenterology and Hepatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
    • ,
  • Markus Mitterhauser

      Affiliations

    • Department of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
    • ,
  • Alfred Gangl

      Affiliations

    • Department of Gastroenterology and Hepatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
    • ,
  • Markus Peck-Radosavljevic

      Affiliations

    • Department of Gastroenterology and Hepatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
    • Corresponding Author InformationCorresponding author. Tel.: +43 1 404006589; fax: +43 1 404004735.

Received 24 February 2009 ,Revised 9 June 2009 ,Accepted 18 June 2009.

References 

  1. Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol. 2003;38(suppl 1):S54–S68
  2. Garcia-Tsao G. Portal hypertension. Curr Opin Gastroenterol. 2006;22:254–262
  3. Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology. 2006;43:S121–S131
  4. Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet. 2003;361:952–954
  5. Johnson DH, Cunha BA. Infections in cirrhosis. Infect Dis Clin North Am. 2001;15:363–371vii
  6. Gines P, Guevara M, Arroyo V, Rodes J. Hepatorenal syndrome. Lancet. 2003;362:1819–1827
  7. Cahill PA, Redmond EM, Sitzmann JV. Endothelial dysfunction in cirrhosis and portal hypertension. Pharmacol Ther. 2001;89:273–293
  8. Hennenberg M, Trebicka J, Sauerbruch T, Heller J. Mechanisms of extrahepatic vasodilation in portal hypertension. Gut. 2008;57:1300–1314
  9. Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC, Rodes J, Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol. 2005;43:98–103
  10. Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J, Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology. 2004;126:886–894
  11. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438:967–974
  12. Fernandez M, Mejias M, Garcia-Pras E, Mendez R, Garcia-Pagan JC, Bosch J. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology. 2007;46:1208–1217
  13. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–7109
  14. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–134
  15. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390
  16. Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology. 2009;49:1066–1068
  17. Hennenberg M, Trebicka J, Stark C, Kohistani AZ, Heller J, Sauerbruch T. Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis. Br J Pharmacol. 2009;157:258–270
  18. Angermayr B, Fernandez M, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J. NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperaemia in portal hypertensive rats. Gut. 2007;56:560–564
  19. Abraldes JG, Iwakiri Y, Loureiro-Silva M, Haq O, Sessa WC, Groszmann RJ. Mild increases in PP upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol. 2006;290:G980–G987
  20. Angermayr B, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J, Fernandez M. Heme oxygenase attenuates oxidative stress and inflammation, and increases VEGF expression in portal hypertensive rats. J Hepatol. 2006;44:1033–1039
  21. Tugues S, Fernandez-Varo G, Munoz-Luque J, Ros J, Arroyo V, Rodes J, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology. 2007;46:1919–1926
  22. Angermayr B, Reiberger T, Rohr-Udilova N, Mitterhauser M, Cejka D, Peck-Radosavljevic M. Angiogenesis in portal hypertensive NAD(P)H-oxidase-knockout-mice is mediated by a different pathway than in wildtype animals [abstract 244]. J Hepatol. 2008;48(suppl 2):S99
  23. Fernandez M, Garcia-Pagan JC, Casadevall M, Mourelle MI, Pique JM, Bosch J, et al. Acute and chronic cyclooxygenase blockage in portal-hypertensive rats: influence in nitric oxide biosynthesis. Gastroenterology. 1996;110:1529–1535
  24. Hou MC, Cahill PA, Zhang S, Wang YN, Hendrickson RJ, Redmond EM, et al. Enhanced cyclooxygenase-1 expression within the superior mesenteric artery of portal hypertensive rats: role in the hyperdynamic circulation. Hepatology. 1998;27:20–27
  25. Carpenter G, Cohen S. Epidermal growth factor. J Biol Chem. 1990;265:7709–7712
  26. Dreux AC, Lamb DJ, Modjtahedi H, Ferns GA. The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis. Atherosclerosis. 2006;186:38–53
  27. Chittenden TW, Sherman JA, Xiong F, Hall AE, Lanahan AA, Taylor JM, et al. Transcriptional profiling in coronary artery disease: indications for novel markers of coronary collateralization. Circulation. 2006;114:1811–1820
  28. Camma C, Petta S, Di Marco V, Bronte F, Ciminnisi S, Licata G, et al. Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis. Hepatology. 2009;49:195–203
  29. Sajid M, Stouffer GA. The role of alpha(v)beta3 integrins in vascular healing. Thromb Haemost. 2002;87:187–193
  30. Dill MT, Djonov V, Hlushchuck R, Tornillo L, Radtke F, Meili-Butz S, et al. Loss of Notch-1 signaling leads to portal hypertension and dedifferentiation of the adult hepatic sinusoidal microvasculature [AASLD abstract 415]. Hepatology. 2008;48(suppl 1):236A

☆ The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript and they do not have a relationship with the manufacturers of the drugs involved either in the past or present.

PII: S0168-8278(09)00518-2

doi: 10.1016/j.jhep.2009.06.024

Journal of Hepatology
Volume 51, Issue 5 , Pages 865-873 , November 2009

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