Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH
| العنوان: | Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH |
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| المؤلفون: | Joan Genescà, Salvador Augustin, Mar Gil, María Martell, Imma Raurell, Diana Hide, Aurora Barberá, Federico Estrella, María Teresa Salcedo, Miren Bravo |
| المساهمون: | Institut Català de la Salut, [Bravo M, Barberá A, Gil M, Estrella F] Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Raurell I, Hide D, Augustin S, Genescà J, Martell M] Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain. [Salcedo MT] Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| المصدر: | Disease Models & Mechanisms article-version (VoR) Version of Record Disease Models & Mechanisms, Vol 14, Iss 5 (2021) Scientia Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona |
| بيانات النشر: | The Company of Biologists, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Liver Cirrhosis, 0301 basic medicine, Contraction (grammar), Atorvastatin, Medicine (miscellaneous), Pharmacology, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Weight Gain, chemistry.chemical_compound, 0302 clinical medicine, Immunology and Microbiology (miscellaneous), Non-alcoholic Fatty Liver Disease, Enos, Pathology, RB1-214, Endothelin-1, NAFLD-NASH, Phenylpropionates, biology, Alanine Transaminase, Drug Synergism, Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::Rats [ORGANISMS], enfermedades del sistema digestivo::enfermedades hepáticas [ENFERMEDADES], Pyridazines, Liver, Medicine, 030211 gastroenterology & hepatology, Collagen, Research Article, medicine.drug, Nitric Oxide Synthase Type III, Ambrisentan, Neuroscience (miscellaneous), Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], General Biochemistry, Genetics and Molecular Biology, Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratas [ORGANISMOS], Nitric oxide, 03 medical and health sciences, Hepatic stellate cells, Rates, medicine, Animals, Liver sinusoidal endothelial cells, Rat as a Disease Model, Fetge - Malalties - Tractament, Hemodynamics, Endothelial Cells, nutritional and metabolic diseases, medicine.disease, biology.organism_classification, Endothelin 1, Enzyme Activation, Disease Models, Animal, Digestive System Diseases::Liver Diseases [DISEASES], 030104 developmental biology, chemistry, Metabolic Disorders, Hepatic stellate cell, Insulin Resistance, Steatohepatitis, Biomarkers |
| الوصف: | In non-alcoholic steatohepatitis (NASH), decreased nitric oxide and increased endothelin-1 (ET-1, also known as EDN1) released by sinusoidal endothelial cells (LSEC) induce hepatic stellate cell (HSC) contraction and contribute to portal hypertension (PH). Statins improve LSEC function, and ambrisentan is a selective endothelin-receptor-A antagonist. We aimed to analyse the combined effects of atorvastatin and ambrisentan on liver histopathology and hemodynamics, together with assessing the underlying mechanism in a rat NASH model. Diet-induced NASH rats were treated with atorvastatin (10 mg/kg/day), ambrisentan (30 mg/kg/day or 2 mg/kg/day) or a combination of both for 2 weeks. Hemodynamic parameters were registered and liver histology and serum biochemical determinations analysed. Expression of proteins were studied by immunoblotting. Conditioned media experiments were performed with LSEC. HSCs were characterized by RT-PCR, and a collagen lattice contraction assay was performed. Atorvastatin and ambrisentan act synergistically in combination to completely normalize liver hemodynamics and reverse histological NASH by 75%. Atorvastatin reversed the sinusoidal contractile phenotype, thus improving endothelial function, whereas ambrisentan prevented the contractile response in HSCs by blocking ET-1 response. Additionally, ambrisentan also increased eNOS (also known as Nos3) phosphorylation levels in LSEC, via facilitating the stimulation of endothelin-receptor-B in these cells. Furthermore, the serum alanine aminotransferase of the combined treatment group decreased to normal levels, and this group exhibited a restoration of the HSC quiescent phenotype. The combination of atorvastatin and ambrisentan remarkably improves liver histology and PH in a diet-induced NASH model. By recovering LSEC function, together with inhibiting the activation and contraction of HSC, this combined treatment may be an effective treatment for NASH patients. Summary: Combining atorvastatin with ambrisentan is safe and effective in reducing intrahepatic resistance and portal hypertension in an experimental model of NASH. This liver histology amelioration highlights a promising therapeutic strategy. |
| وصف الملف: | application/pdf |
| تدمد: | 1754-8411 1754-8403 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ca1c507db803d0ab75718846650967acTest https://doi.org/10.1242/dmm.048884Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ca1c507db803d0ab75718846650967ac |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17548411 17548403 |
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