Long-term treatment of bile duct-ligated rats with rapamycin (sirolimus) significantly attenuates liver fibrosis: analysis of the underlying mechanisms
| Autor: | Markus Neef, Jürg Reichen, Hans Sägesser, Andrea De Gottardi, Erwin Biecker, Sidney Shaw, M. Ledermann, Vreni Schneider, Matthias Unternährer |
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| Rok vydání: | 2005 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Male medicine.medical_specialty medicine.medical_treatment Connective tissue P70-S6 Kinase 1 Cell Cycle Proteins Biology Liver Cirrhosis Experimental digestive system Immediate-Early Proteins Transforming Growth Factor beta1 Transforming Growth Factor beta Internal medicine medicine Animals Phosphorylation Rats Wistar Ligation Cell Proliferation Pharmacology Sirolimus Kinase Growth factor Tumor Suppressor Proteins Connective Tissue Growth Factor Rats CTGF Endocrinology medicine.anatomical_structure biology.protein Molecular Medicine Intercellular Signaling Peptides and Proteins Bile Ducts Platelet-derived growth factor receptor Cyclin-Dependent Kinase Inhibitor p27 Transforming growth factor medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 313(3) |
| ISSN: | 0022-3565 |
| Popis: | Rapamycin is an immunosuppressant with antiproliferative properties. We investigated whether rapamycin treatment of bile duct-ligated (BDL) rats is capable of inhibiting liver fibrosis and thereby affecting hemodynamics. Following BDL, rats were treated for 28 days with rapamycin (BDL SIR). BDL animals without drug treatment (BDL CTR) and sham-operated animals served as controls. After 28 days, hemodynamics were measured, and livers were harvested for histology/immunohistochemistry. Liver mRNA levels of transforming growth factor (TGF)-beta1, connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF)-beta, cyclin-dependent kinase inhibitor p27(kip) (p27), and cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) were quantified by real-time polymerase chain reaction. Liver protein levels of p27, p21, p70 S6 kinase (p70(s6k)), phosphorylated p70(s6k) (p-p70(s6k)), eukaryotic initiation factor 4E-binding protein (4E-BP1), p-4E-BP1 (Thr37/46), and p-4E-BP1 (Ser65/Thr70) were determined by Western blotting. Portal vein pressure was lower in BDL SIR than in BDL CTR animals. Volume fractions of connective tissue, bile duct epithelial, and desmin- and actin-positive cells were lower in BDL SIR than in BDL CTR rats. On the mRNA level, TGF-beta1, CTGF, and PDGF were decreased by rapamycin. p27 and p21 mRNA did not differ. On the protein level, rapamycin increased p27 and decreased p21 levels. Levels of nonphosphorylated p70(s6k) and 4E-BP1 did not vary between groups, but levels of p-p70(s6k) were decreased by rapamycin. Rapamycin had no effect on p-4E-BP1 (Thr37/46) and p-4E-BP1 (Ser65/Thr70) levels. In BDL rats, rapamycin inhibits liver fibrosis and ameliorates portal hypertension. This is paralleled by decreased levels of TGF-beta1, CTGF, and PDGF. Rapamycin influences the cell cycle by up-regulation of p27, down-regulation of p21, and inhibition of p70(s6k) phosphorylation. |
| Databáze: | OpenAIRE |
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