Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts

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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34 Citations (Scopus)


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 72. h. 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.

Original languageEnglish
Pages (from-to)57-64
Number of pages8
JournalToxicology and Applied Pharmacology
Issue number1
Publication statusPublished - 15 Aug 2011


  • Apoptosis
  • Cell death
  • Fibroblast
  • Heart
  • HMG coA reductase
  • Myofibroblast
  • Rho A
  • Statin

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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