Article Text

PDF
Intrahepatic upregulation of RhoA and Rho-kinase signalling contributes to increased hepatic vascular resistance in rats with secondary biliary cirrhosis
  1. Q Zhou*,
  2. M Hennenberg*,
  3. J Trebicka,
  4. K Jochem,
  5. L Leifeld,
  6. E Biecker,
  7. T Sauerbruch,
  8. J Heller
  1. Department of Internal Medicine I, University of Bonn, Bonn, Germany
  1. Correspondence to:
    Martin Hennenberg
    Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str 25, D-53105 Bonn, Germany; Martin.Hennenberg{at}ukb.uni-bonn.de

Abstract

Background and aims: Portal hypertension in cirrhosis is mediated in part by increased intrahepatic resistance, reflecting an increased sensitivity of the hepatic microvasculature to vasoconstrictors. Activation of the RhoA/Rho-kinase pathway is essential for contraction of vascular smooth muscle. The aim of this study was to investigate RhoA/Rho-kinase mediated regulation of the intrahepatic vascular tone in cirrhotic rats.

Methods: Cirrhosis was induced by bile duct ligation (BDL). Hepatic RhoA and Rho-kinase expressions were studied by real time reverse transcription polymerase chain reaction and western blot analysis. Hepatic Rho-kinase activity in rat and human livers was assessed as phosphorylation of the Rho-kinase substrate moesin. The effect of the Rho-kinase inhibitor Y-27632 on hepatic perfusion pressure was measured in livers perfused at constant flow. The in vivo effect of intravenous application of Y-27632 was studied by haemodynamic measurements.

Results: Hepatic expressions of RhoA and Rho-kinase were increased at mRNA and protein level in BDL rats. Intrahepatic moesin phosphorylation was increased in livers from cirrhotic rats and patients with alcohol induced cirrhosis. Y-27632 reduced the basal perfusion pressure of in situ perfused livers in BDL rats but not in sham operated rats. Y-27632 reduced the sensitivity to methoxamine in isolated perfused livers in sham operated rats more than in BDL rats. In vivo, Y-27632 reduced portal pressure to a greater extent in BDL rats than in sham operated rats. Intrahepatic vascular resistance was decreased in response to bolus injection of Y-27632 in BDL rats but not in sham operated rats.

Conclusions: Upregulation of RhoA and Rho-kinase contributes to increased intrahepatic resistance in cirrhotic rats and to an increased sensitivity of cirrhotic livers to vasoconstrictors.

  • BDL, bile duct ligation
  • EC50, concentration producing a half maximal effect
  • HSC, hepatic stellate cell
  • PSS, porto-systemic shunting
  • RT-PCR, real time reverse transcription polymerase chain reaction
  • Y-27632, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexane carboxamide dihydrochloride, monohydrate
  • cirrhosis
  • portal hypertension
  • intrahepatic vascular resistance
  • RhoA
  • Rho-kinase

Statistics from Altmetric.com

Footnotes

  • Published online first 21 February 2006

  • * QZ and MH contributed equally to this paper.

  • Conflict of interest: None declared.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.