Intrahepatic upregulation of RhoA and Rho-kinase signalling contributes to increased hepatic vascular resistance in rats with secondary biliary cirrhosis. Issue 9 (21st February 2006)

• Record Type: Journal Article
• Authors: Zhou, Q; Hennenberg, M; Trebicka, J; Jochem, K; Leifeld, L; Biecker, E; Sauerbruch, T; Heller, J
• Is Part Of: Gut. Volume 55:Issue 9(2006)
• Page Start: 1296
• Page End: 1305
• Publication Date: 2006-02-21
• Subjects: 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; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2005.081059
• Languages: English
• ISSNs: 0017-5749

Abstract

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.