| Intrahepatic upregulation of RhoA and Rho-kinase signalling contributes to increased hepatic vascular resistance in rats with secondary biliary cirrhosis. | |
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MedLine Citation:
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PMID: 16492715 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Q Zhou; M Hennenberg; J Trebicka; K Jochem; L Leifeld; E Biecker; T Sauerbruch; J Heller |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-02-21 |
Journal Detail:
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Title: Gut Volume: 55 ISSN: 0017-5749 ISO Abbreviation: Gut Publication Date: 2006 Sep |
Date Detail:
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Created Date: 2006-08-14 Completed Date: 2006-09-21 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 2985108R Medline TA: Gut Country: England |
Other Details:
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Languages: eng Pagination: 1296-305 Citation Subset: AIM; IM |
Affiliation:
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Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str 25, D-53105 Bonn, Germany. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Dose-Response Relationship, Drug Hemodynamics / drug effects Hypertension, Portal / etiology, physiopathology Intracellular Signaling Peptides and Proteins Liver / metabolism Liver Circulation* Liver Cirrhosis, Biliary / complications, metabolism*, physiopathology Male Methoxamine / pharmacology Microfilament Proteins / metabolism Phosphorylation Protein-Serine-Threonine Kinases / antagonists & inhibitors, biosynthesis*, genetics Rats Rats, Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction / methods Signal Transduction Up-Regulation Vascular Resistance Vasoconstrictor Agents / pharmacology rho-Associated Kinases rhoA GTP-Binding Protein / biosynthesis*, genetics |
| Chemical | |
Reg. No./Substance:
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0/Intracellular Signaling Peptides and Proteins; 0/Microfilament Proteins; 0/Vasoconstrictor Agents; 144131-77-1/moesin; 390-28-3/Methoxamine; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/rho-Associated Kinases; EC 3.6.5.2/rhoA GTP-Binding Protein |
| Comments/Corrections | |
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