Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats
Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile duct-ligated (BDL) rats in vivo. Here, we have further investigate...
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Published in | Laboratory investigation Vol. 92; no. 10; pp. 1440 - 1450 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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New York
Elsevier Inc
01.10.2012
Nature Publishing Group US Nature Publishing Group |
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Abstract | Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile duct-ligated (BDL) rats in vivo. Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10−4, 10−5 and 10−6 M), transcription levels of profibrotic cytokines (transforming growth factor-β1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. α-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and β-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15 mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro. In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10−4 M and attenuated it at 10−5 M. Atorvastatin induced p21 protein expression and β-galactosidase staining of MFB in vitro and in vivo. Atorvastatin elicits similiar effects on MFB as previously seen in vivo: it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells. |
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AbstractList | Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile duct-ligated (BDL) rats in vivo. Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10(-4), 10(-5) and 10(-6) M), transcription levels of profibrotic cytokines (transforming growth factor-β1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. α-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and β-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15 mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro. In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10(-4) M and attenuated it at 10(-5) M. Atorvastatin induced p21 protein expression and β-galactosidase staining of MFB in vitro and in vivo. Atorvastatin elicits similiar effects on MFB as previously seen in vivo: it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells. Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile duct-ligated (BDL) rats in vivo. Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10−4, 10−5 and 10−6 M), transcription levels of profibrotic cytokines (transforming growth factor-β1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. α-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and β-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15 mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro. In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10−4 M and attenuated it at 10−5 M. Atorvastatin induced p21 protein expression and β-galactosidase staining of MFB in vitro and in vivo. Atorvastatin elicits similiar effects on MFB as previously seen in vivo: it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells. Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile duct-ligated (BDL) rats in vivo . Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10 −4 , 10 −5 and 10 −6 M), transcription levels of profibrotic cytokines (transforming growth factor-β1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. α-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and β-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15 mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro . In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10 −4 M and attenuated it at 10 −5 M. Atorvastatin induced p21 protein expression and β-galactosidase staining of MFB in vitro and in vivo . Atorvastatin elicits similiar effects on MFB as previously seen in vivo : it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells. Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile duct-ligated (BDL) rats in vivo. Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10(-4), 10(-5) and 10(-6) M), transcription levels of profibrotic cytokines (transforming growth factor-[beta]1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. α-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and [beta]-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15 mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro. In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10(-4) M and attenuated it at 10(-5) M. Atorvastatin induced p21 protein expression and [beta]-galactosidase staining of MFB in vitro and in vivo. Atorvastatin elicits similiar effects on MFB as previously seen in vivo: it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells. |
Author | Pieper-Fürst, Ursula Klösel, Jeremias Körner, Christian Granzow, Michaela Fürst, Dieter O Mazar, Irela Gretchen Reza Huss, Sebastian Klein, Sabine Lammert, Frank van den Ven, Peter F M Weber, Susanne Trebicka, Jonel Schierwagen, Robert Nattermann, Jacob Sauerbruch, Tilman |
Author_xml | – sequence: 1 givenname: Sabine surname: Klein fullname: Klein, Sabine organization: Department of Internal Medicine I, University of Bonn, Bonn, Germany – sequence: 2 givenname: Jeremias surname: Klösel fullname: Klösel, Jeremias organization: Department of Internal Medicine I, University of Bonn, Bonn, Germany – sequence: 3 givenname: Robert surname: Schierwagen fullname: Schierwagen, Robert organization: Department of Internal Medicine I, University of Bonn, Bonn, Germany – sequence: 4 givenname: Christian surname: Körner fullname: Körner, Christian organization: Department of Internal Medicine I, University of Bonn, Bonn, Germany – sequence: 5 givenname: Michaela surname: Granzow fullname: Granzow, Michaela organization: Department of Internal Medicine I, University of Bonn, Bonn, Germany – sequence: 6 givenname: Sebastian surname: Huss fullname: Huss, Sebastian organization: Department of Pathology, University of Bonn, Bonn, Germany – sequence: 7 givenname: Irela Gretchen Reza surname: Mazar fullname: Mazar, Irela Gretchen Reza organization: Institute for Cell Biology, University of Bonn, Bonn, Germany – sequence: 8 givenname: Susanne surname: Weber fullname: Weber, Susanne organization: Department of Medicine II, Saarland University Medical Center, Homburg, Germany – sequence: 9 givenname: Peter F M surname: van den Ven fullname: van den Ven, Peter F M organization: Institute for Cell Biology, University of Bonn, Bonn, Germany – sequence: 10 givenname: Ursula surname: Pieper-Fürst fullname: Pieper-Fürst, Ursula organization: Department of Internal Medicine I, University of Bonn, Bonn, Germany – sequence: 11 givenname: Dieter O surname: Fürst fullname: Fürst, Dieter O organization: Institute for Cell Biology, University of Bonn, Bonn, Germany – sequence: 12 givenname: Jacob surname: Nattermann fullname: Nattermann, Jacob organization: Department of Internal Medicine I, University of Bonn, Bonn, Germany – sequence: 13 givenname: Frank surname: Lammert fullname: Lammert, Frank organization: Department of Medicine II, Saarland University Medical Center, Homburg, Germany – sequence: 14 givenname: Tilman surname: Sauerbruch fullname: Sauerbruch, Tilman organization: Department of Internal Medicine I, University of Bonn, Bonn, Germany – sequence: 15 givenname: Jonel surname: Trebicka fullname: Trebicka, Jonel email: jonel.trebicka@ukb.uni-bonn.de organization: Department of Internal Medicine I, University of Bonn, Bonn, Germany |
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Copyright | 2012 United States & Canadian Academy of Pathology United States and Canadian Academy of Pathology, Inc. 2012 2015 INIST-CNRS Copyright Nature Publishing Group Oct 2012 |
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Keywords | senescence hepatic stellate cells cytokines fibrogenesis myofibroblasts HMG-CoA reductase inhibitor Cell proliferation Biotechnology Senescence Rat Liver Myofibroblast Hepatic disease Hypocholesterolemic agent Clinical biology Hepatic fibrosis Digestive system Enzyme Rodentia Cytokine Enzyme inhibitor Statin derivative Kupffer cell Vertebrata Mammalia Cell death Animal Atorvastatin Digestive diseases Hydroxymethylglutaryl-CoA reductase Oxidoreductases Apoptosis Antilipemic agent |
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Publisher | Elsevier Inc Nature Publishing Group US Nature Publishing Group |
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SubjectTerms | 631/80/509 631/92/609 692/699/1503/1607/1605 Actins - immunology Actins - metabolism Aging - drug effects Animals Apoptosis - drug effects Atorvastatin beta-Galactosidase - analysis beta-Galactosidase - metabolism Biological and medical sciences Biotechnology Cell Proliferation - drug effects Collagen - metabolism Connective Tissue Growth Factor - genetics Connective Tissue Growth Factor - metabolism cytokines Desmin - immunology Desmin - metabolism Dose-Response Relationship, Drug fibrogenesis Flow Cytometry Fundamental and applied biological sciences. Psychology Gastroenterology. Liver. Pancreas. Abdomen hepatic stellate cells Hepatic Stellate Cells - drug effects Heptanoic Acids - pharmacology HMG-CoA reductase inhibitor Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology Investigative techniques, diagnostic techniques (general aspects) Laboratory Medicine Liver - cytology Liver - drug effects Liver - metabolism Liver Cirrhosis - drug therapy Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Medicine Medicine & Public Health myofibroblasts Myofibroblasts - drug effects Other diseases. Semiology Pathology Pyrroles - pharmacology Rats Rats, Sprague-Dawley research-article senescence Tissue Inhibitor of Metalloproteinase-1 - genetics Tissue Inhibitor of Metalloproteinase-1 - metabolism Transforming Growth Factor beta1 - genetics Transforming Growth Factor beta1 - metabolism |
Title | Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats |
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