Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts
- Centro FONDAP Estudios Moleculares de la Celula, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santiago (Chile)
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 (0.1-10 {mu}M) 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. - Research Highlights: > Simvastatin decreases CF and CMF viability independent of cholesterol synthesis. > Simvastatin induces CF and CMF apoptosis in a caspase-dependent manner being CMF more resistant than CF. > CMF has higher expression and active RhoA protein levels.
- OSTI ID:
- 21587821
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 255, Issue 1; Other Information: DOI: 10.1016/j.taap.2011.05.016; PII: S0041-008X(11)00204-3; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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APOPTOSIS
CARBONYLS
CARDIOVASCULAR DISEASES
CATTLE
CHOLESTEROL
CLINICAL TRIALS
COENZYMES
FIBROBLASTS
FLUORESCENCE
GROWTH FACTORS
HEART
MUSCLES
RATS
SQUALENE
TIME DEPENDENCE
TRYPAN BLUE
VIABILITY
AMINES
ANIMAL CELLS
ANIMALS
AROMATICS
AZO COMPOUNDS
AZO DYES
BODY
CARDIOVASCULAR SYSTEM
CONNECTIVE TISSUE CELLS
DISEASES
DOMESTIC ANIMALS
DYES
EMISSION
HYDROCARBONS
HYDROXY COMPOUNDS
LUMINESCENCE
MAMMALS
MITOGENS
NAPHTHOLS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
PHENOLS
PHOTON EMISSION
POLYENES
PROTEINS
RODENTS
RUMINANTS
SOMATIC CELLS
STEROIDS
STEROLS
SULFONIC ACIDS
TERPENES
TESTING
VERTEBRATES