| Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver. | |
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MedLine Citation:
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PMID: 18795901 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND/OBJECTIVE: Carbon monoxide (CO) produced by haem-oxygenase isoforms (HO-1 & HO-2) is involved in the regulation of systemic vascular tone. We aimed to elucidate the vasoregulatory role of CO in the microcirculation in normal and thioacetamide cirrhotic rat livers. METHODS: Haem-oxygenase expression was examined by Western blot. Total HO enzymatic activity was measured spectrophotometrically. Sensitivity of hepatic stellate cells (HSCs) to CO-mediated relaxation was studied by a stress-relaxed-collagen-lattice model. To define the relative role of CO, the CO-releasing molecule CORM-2, the HO-inhibitor zinc protoporphyrin-IX and the HO-1 inducer hemin were added to an in situ liver perfusion set-up. The topography of vasoactive CO production was evaluated by applying different CO- and nitric oxide-trapping reagents in the liver perfusion set-up and by immunohistochemistry. RESULTS: Western blot showed decreased expression of both HO isoenzymes (P<0.036 for HO-1; P<0.001 for HO-2) in cirrhotic vs normal rat livers, confirmed by the HO-activity assay (P=0.004). HSCs relaxed on exposure to CORM-2 (P=0.013). The increased intrahepatic vascular resistance (IHVR) of cirrhotic rats was attenuated by perfusion with CORM-2 (P=0.016) and pretreatment with hemin (P<0.001). Inhibition of HO caused a dose-related increase in IHVR in normal and cirrhotic liver. In normal liver, the haemodynamically relevant CO production occurred extrasinusoidally, while intrasinusoidally HO-1 predominantly regulated the microcirculation in cirrhotic livers. CONCLUSION: We demonstrate a role for CO and HO in the regulation of normal and cirrhotic microcirculation. These findings are of importance in the pathophysiology of portal hypertension and establish CO/HO as novel treatment targets. |
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Authors:
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Lien Van Landeghem; Wim Laleman; Ingrid Vander Elst; Marcel Zeegers; Jos van Pelt; David Cassiman; Frederik Nevens |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-09-15 |
Journal Detail:
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Title: Liver international : official journal of the International Association for the Study of the Liver Volume: 29 ISSN: 1478-3231 ISO Abbreviation: Liver Int. Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-05-05 Completed Date: 2009-08-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101160857 Medline TA: Liver Int Country: England |
Other Details:
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Languages: eng Pagination: 650-60 Citation Subset: IM |
Affiliation:
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Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western Carbon Monoxide / metabolism* Heme Oxygenase-1 / metabolism* Hemin Hemodynamics / physiology* Hepatic Stellate Cells / physiology Liver Cirrhosis / enzymology* Models, Biological Organometallic Compounds Rats |
| Chemical | |
Reg. No./Substance:
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0/Organometallic Compounds; 0/tricarbonyldichlororuthenium (II) dimer; 16009-13-5/Hemin; 630-08-0/Carbon Monoxide; EC 1.14.99.3/Heme Oxygenase-1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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