| Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts. | |
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MedLine Citation:
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PMID: 21651924 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Several clinical trials have shown the beneficial effects of statins in the prevention of coronary heart disease. Additionally, statins promote apoptosis in vascular smooth muscle cells, in renal tubular epithelial cells and also in a variety of cell lines; yet, the effects of statins on cardiac fibroblast and myofibroblast, primarily responsible for cardiac tissue healing are almost unknown. Here, we investigated the effects of simvastatin on cardiac fibroblast and myofibroblast viability and studied the molecular cell death mechanism triggered by simvastatin in both cell types. METHODS: Rat neonatal cardiac fibroblasts and myofibroblasts were treated with simvastatin (0.1-10μM) up to 72h. Cell viability and apoptosis were evaluated by trypan blue exclusion method and by flow cytometry, respectively. Caspase-3 activation and Rho protein levels and activity were also determined by Western blot and pull-down assay, respectively. RESULTS: Simvastatin induces caspase-dependent apoptosis of cardiac fibroblasts and myofibroblasts in a concentration- and time-dependent manner, with greater effects on fibroblasts than myofibroblasts. These effects were prevented by mevalonate, farnesylpyrophosphate and geranylgeranylpyrophosphate, but not squalene. These last results suggest that apoptosis was dependent on small GTPases of the Rho family rather than Ras. CONCLUSION: Simvastatin triggered apoptosis of cardiac fibroblasts and myofibroblasts by a mechanism independent of cholesterol synthesis, but dependent of isoprenilation of Rho protein. Additionally, cardiac fibroblasts were more susceptible to simvastatin-induced apoptosis than cardiac myofibroblasts. Thus simvastatin could avoid adverse cardiac remodeling leading to a less fibrotic repair of the damaged tissues. |
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Authors:
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Miguel Copaja; Daniel Venegas; Pablo Aránguiz; Jimena Canales; Raúl Vivar; Mabel Catalán; Ivonne Olmedo; Andrea E Rodríguez; Mario Chiong; Lisette Leyton; Sergio Lavandero; Guillermo Díaz-Araya |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-30 |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: - ISSN: 1096-0333 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-6-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier Inc. |
Affiliation:
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Centro FONDAP Estudios Moleculares de la Célula, Facultad Ciencias Químicas y Farmacéuticas, Chile. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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