Comparison of endothelin receptors in normal versus cirrhotic human liver and in the liver from endothelial cell-specific ETB knockout mice
Copyright © 2012 Elsevier Inc. All rights reserved..
AIMS: Endothelin (ET) antagonists show promise in animal models of cirrhosis and portal hypertension. The aim was to pharmacologically characterise the expression of endothelin receptors in human liver, hepatic artery and portal vein.
MAIN METHODS: Immunofluorescence staining, receptor autoradiography and competition binding assays were used to localise and quantify ET receptors on hepatic parenchyma, hepatic artery and portal vein in human cirrhotic or normal liver. Additional experiments were performed to determine the affinity and selectivity of ET antagonists for liver ET endothelin receptors. An endothelial cell ET(B) knockout murine model was used to examine the function of sinusoid endothelial ET(B) receptors.
KEY FINDINGS: ET(B) receptors predominated in normal human liver and displayed the highest ratio (ET(B):ET(A) 63:47) compared with other peripheral tissues. In two patients examined, liver ET(B) expression was up-regulated in cirrhosis (ET(B):ET(A) 83:17). Both sub-types localised to the media of normal portal vein but ET(B) receptors were downregulated fivefold in the media of cirrhotic portal vein. Sinusoid diameter was fourfold smaller in endothelial cell ET(B) knockout mice. The liver morphology of ET(B) knockout mice was markedly different to normal murine liver, with loss of the wide spread sinusoidal pattern. In the knockout mice, sinusoids were reduced in both number and absolute diameter, while large intrahepatic veins were congested with red blood cells.
SIGNIFICANCE: These data support a role for the ET system in cirrhosis of the liver and suggest that endothelial ET(B) blockade may cause sinusoidal constriction which may contribute to hepatotoxicity associated with some endothelin antagonists.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2012 |
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| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:91 |
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| Enthalten in: |
Life sciences - 91(2012), 13-14 vom: 15. Okt., Seite 716-22 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ling, Lowell [VerfasserIn] |
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| Links: |
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| Themen: |
Ambrisentan |
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| Anmerkungen: |
Date Completed 07.01.2013 Date Revised 09.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.lfs.2012.02.003 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM215724410 |
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| 100 | 1 | |a Ling, Lowell |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Comparison of endothelin receptors in normal versus cirrhotic human liver and in the liver from endothelial cell-specific ETB knockout mice |
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| 500 | |a Date Revised 09.04.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2012 Elsevier Inc. All rights reserved. | ||
| 520 | |a AIMS: Endothelin (ET) antagonists show promise in animal models of cirrhosis and portal hypertension. The aim was to pharmacologically characterise the expression of endothelin receptors in human liver, hepatic artery and portal vein | ||
| 520 | |a MAIN METHODS: Immunofluorescence staining, receptor autoradiography and competition binding assays were used to localise and quantify ET receptors on hepatic parenchyma, hepatic artery and portal vein in human cirrhotic or normal liver. Additional experiments were performed to determine the affinity and selectivity of ET antagonists for liver ET endothelin receptors. An endothelial cell ET(B) knockout murine model was used to examine the function of sinusoid endothelial ET(B) receptors | ||
| 520 | |a KEY FINDINGS: ET(B) receptors predominated in normal human liver and displayed the highest ratio (ET(B):ET(A) 63:47) compared with other peripheral tissues. In two patients examined, liver ET(B) expression was up-regulated in cirrhosis (ET(B):ET(A) 83:17). Both sub-types localised to the media of normal portal vein but ET(B) receptors were downregulated fivefold in the media of cirrhotic portal vein. Sinusoid diameter was fourfold smaller in endothelial cell ET(B) knockout mice. The liver morphology of ET(B) knockout mice was markedly different to normal murine liver, with loss of the wide spread sinusoidal pattern. In the knockout mice, sinusoids were reduced in both number and absolute diameter, while large intrahepatic veins were congested with red blood cells | ||
| 520 | |a SIGNIFICANCE: These data support a role for the ET system in cirrhosis of the liver and suggest that endothelial ET(B) blockade may cause sinusoidal constriction which may contribute to hepatotoxicity associated with some endothelin antagonists | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Alexander, Graeme J M |e verfasserin |4 aut | |
| 700 | 1 | |a Davenport, Anthony P |e verfasserin |4 aut | |
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