The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage
Sabrina Ehnert,1 Teresa Lukoschek,2 Anastasia Bachmann,2 Juan J Martínez Sánchez,1 Georg Damm,3 Natascha C Nussler,4 Stefan Pscherer,5 Ulrich Stöckle,1 Steven Dooley,2 Sebastian Mueller,6 Andreas K Nussler11Eberhard Karls Universität Tübingen, BG Trau...
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Dove Medical Press
2013
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oai:doaj.org-article:5aefdb356ef64a6da5bba941c484b62a2021-12-02T04:12:20ZThe right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage1179-1535https://doaj.org/article/5aefdb356ef64a6da5bba941c484b62a2013-03-01T00:00:00Zhttp://www.dovepress.com/the-right-choice-of-antihypertensives-protects-primary-human-hepatocyt-a12549https://doaj.org/toc/1179-1535Sabrina Ehnert,1 Teresa Lukoschek,2 Anastasia Bachmann,2 Juan J Martínez Sánchez,1 Georg Damm,3 Natascha C Nussler,4 Stefan Pscherer,5 Ulrich Stöckle,1 Steven Dooley,2 Sebastian Mueller,6 Andreas K Nussler11Eberhard Karls Universität Tübingen, BG Trauma Center, Tübingen, Germany; 2Mol Hepatology - Alcohol Associated Diseases, Department of Medicine II, Medical Faculty, Mannheim, Germany; 3Department of General, Visceral, and Transplantation Surgery, Charité University Medicine, Berlin, Germany; 4Clinic for General, Visceral, Endocrine Surgery and Coloproctology, Clinic Neuperlach, Städtisches Klinikum München GmbH, Munich, Germany; 5Department of Diabetology, Klinikum Traunstein, Kliniken Südostbayern AG, Traunstein, Germany; 6Department of Medicine, Salem Medical Center, Ruprecht-Karls-Universität, Heidelberg, GermanyBackground: Patients with alcoholic liver disease (ALD) often suffer from high blood pressure and rely on antihypertensive treatment. Certain antihypertensives may influence progression of chronic liver disease. Therefore, the aim of this study is to investigate the impact of the commonly used antihypertensives amlodipine, captopril, furosemide, metoprolol, propranolol, and spironolactone on alcohol-induced damage toward human hepatocytes (hHeps).Methods: hHeps were isolated by collagenase perfusion. Reactive oxygen species (ROS) were measured by fluorescence-based assays. Cellular damage was determined by lactate-dehydrogenase (LDH)-leakage. Expression analysis was performed by reverse-transcription polymerase chain reaction and Western blot. Transforming growth factor (TGF)-β signaling was investigated by a Smad3/4-responsive luciferase-reporter assay.Results: Ethanol and TGF-β1 rapidly increased ROS in hHeps, causing a release of 40%–60% of total LDH after 72 hours. All antihypertensives dose dependently reduced ethanol-mediated oxidative stress and cellular damage. Similar results were observed for TGF-β1-dependent damage, except for furosemide, which had no effect. As a common mechanism, all antihypertensives increased heme-oxygenase-1 (HO-1) expression, and inhibition of HO-1 activity reversed the protective effect of the drugs. Interestingly, Smad3/4 signaling was reduced by all compounds except furosemide, which even enhanced this profibrotic signaling. This effect was mediated by expressional changes of Smad3 and/or Smad4.Conclusions: Our results suggest that antihypertensives may both positively and negatively influence chronic liver disease progression. Therefore, we propose that in future patients with ALD and high blood pressure, they could benefit from an adjusted antihypertensive therapy with additional antifibrotic effects.Keywords: primary human hepatocytes, alcoholic liver disease, ethanol, TGF-β1, antihypertensivesEhnert SLukoschek TBachmann AMartinez Sanchez JJDamm GNussler NCPscherer SStöckle UDooley SMueller SNussler AKDove Medical PressarticleDiseases of the digestive system. GastroenterologyRC799-869ENHepatic Medicine: Evidence and Research, Vol 2013, Iss default, Pp 31-41 (2013) |
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Diseases of the digestive system. Gastroenterology RC799-869 |
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Diseases of the digestive system. Gastroenterology RC799-869 Ehnert S Lukoschek T Bachmann A Martinez Sanchez JJ Damm G Nussler NC Pscherer S Stöckle U Dooley S Mueller S Nussler AK The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage |
| description |
Sabrina Ehnert,1 Teresa Lukoschek,2 Anastasia Bachmann,2 Juan J Martínez Sánchez,1 Georg Damm,3 Natascha C Nussler,4 Stefan Pscherer,5 Ulrich Stöckle,1 Steven Dooley,2 Sebastian Mueller,6 Andreas K Nussler11Eberhard Karls Universität Tübingen, BG Trauma Center, Tübingen, Germany; 2Mol Hepatology - Alcohol Associated Diseases, Department of Medicine II, Medical Faculty, Mannheim, Germany; 3Department of General, Visceral, and Transplantation Surgery, Charité University Medicine, Berlin, Germany; 4Clinic for General, Visceral, Endocrine Surgery and Coloproctology, Clinic Neuperlach, Städtisches Klinikum München GmbH, Munich, Germany; 5Department of Diabetology, Klinikum Traunstein, Kliniken Südostbayern AG, Traunstein, Germany; 6Department of Medicine, Salem Medical Center, Ruprecht-Karls-Universität, Heidelberg, GermanyBackground: Patients with alcoholic liver disease (ALD) often suffer from high blood pressure and rely on antihypertensive treatment. Certain antihypertensives may influence progression of chronic liver disease. Therefore, the aim of this study is to investigate the impact of the commonly used antihypertensives amlodipine, captopril, furosemide, metoprolol, propranolol, and spironolactone on alcohol-induced damage toward human hepatocytes (hHeps).Methods: hHeps were isolated by collagenase perfusion. Reactive oxygen species (ROS) were measured by fluorescence-based assays. Cellular damage was determined by lactate-dehydrogenase (LDH)-leakage. Expression analysis was performed by reverse-transcription polymerase chain reaction and Western blot. Transforming growth factor (TGF)-β signaling was investigated by a Smad3/4-responsive luciferase-reporter assay.Results: Ethanol and TGF-β1 rapidly increased ROS in hHeps, causing a release of 40%–60% of total LDH after 72 hours. All antihypertensives dose dependently reduced ethanol-mediated oxidative stress and cellular damage. Similar results were observed for TGF-β1-dependent damage, except for furosemide, which had no effect. As a common mechanism, all antihypertensives increased heme-oxygenase-1 (HO-1) expression, and inhibition of HO-1 activity reversed the protective effect of the drugs. Interestingly, Smad3/4 signaling was reduced by all compounds except furosemide, which even enhanced this profibrotic signaling. This effect was mediated by expressional changes of Smad3 and/or Smad4.Conclusions: Our results suggest that antihypertensives may both positively and negatively influence chronic liver disease progression. Therefore, we propose that in future patients with ALD and high blood pressure, they could benefit from an adjusted antihypertensive therapy with additional antifibrotic effects.Keywords: primary human hepatocytes, alcoholic liver disease, ethanol, TGF-β1, antihypertensives |
| format |
article |
| author |
Ehnert S Lukoschek T Bachmann A Martinez Sanchez JJ Damm G Nussler NC Pscherer S Stöckle U Dooley S Mueller S Nussler AK |
| author_facet |
Ehnert S Lukoschek T Bachmann A Martinez Sanchez JJ Damm G Nussler NC Pscherer S Stöckle U Dooley S Mueller S Nussler AK |
| author_sort |
Ehnert S |
| title |
The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage |
| title_short |
The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage |
| title_full |
The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage |
| title_fullStr |
The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage |
| title_full_unstemmed |
The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage |
| title_sort |
right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human tgf-β1-induced cellular damage |
| publisher |
Dove Medical Press |
| publishDate |
2013 |
| url |
https://doaj.org/article/5aefdb356ef64a6da5bba941c484b62a |
| work_keys_str_mv |
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