TY - JOUR
T1 - Simvastatin disrupts cytoskeleton and decreases cardiac fibroblast adhesion, migration and viability
AU - Copaja, Miguel
AU - Venegas, Daniel
AU - Aranguiz, Pablo
AU - Canales, Jimena
AU - Vivar, Raul
AU - Avalos, Yennifer
AU - Garcia, Lorena
AU - Chiong, Mario
AU - Olmedo, Ivonne
AU - Catalán, Mabel
AU - Leyton, Lisette
AU - Lavandero, Sergio
AU - Díaz-Araya, Guillermo
N1 - Funding Information:
This work was supported by Comisión Nacional de Ciencia y Tecnología (CONICYT)-Chile [FONDECYT 1061059 to G.D.-A and FONDAP 15010006 to S.L., G.D.A., M.C. and L.G.] and Fondo Mejoramiento de la Calidad de la Educación Superior (MECESUP) UCHO802. MC, PA, RV, IO, and MC hold Ph.D. fellowship from CONICYT, Chile. We also appreciate the excellent technical assistance of Fidel Albornoz. S.L is on a sabbatical leave at the University of Texas Southwestern Medical Center, Dallas, TX, USA.
PY - 2012/3/29
Y1 - 2012/3/29
N2 - Statins reduce the isoprenoids farnesyl and geranylgeranyl pyrophosphate, essential intermediates, which control a diversity of cellular events such as cytoskeleton integrity, adhesion, migration and viability. Cardiac fibroblasts are the major non-myocyte cell constituent in the normal heart, and play a key role in the maintenance of extracellular matrix. The effects of simvastatin on cardiac fibroblast processes previously mentioned remain unknown. Our aims were to investigate the effects of simvastatin on cytoskeleton structure and focal adhesion complex assembly and their relationships with cell adhesion, migration and viability in cultured cardiac fibroblasts. To this end, cells were treated with simvastatin for 24. h and changes in actin cytoskeleton, levels of vimentin and paxillin as well as their subcellular localization were analyzed by Western blot and immunocytochemistry, respectively. Cell adhesion to plastic or collagen coated dishes, migration in Transwell chambers, and cell viability were analyzed after simvastatin treatment. Our results show that simvastatin disrupts actin cytoskeleton and focal adhesion complex evaluated by phalloidin stain and immunocytochemistry for paxillin and vinculin. All these effects occurred by a cholesterol synthesis-independent mechanism. Simvastatin decreased cell adhesion, migration and viability in a concentration-dependent manner. Finally, simvastatin decreased angiotensin II-induced phospho-paxillin levels and cell adhesion. We concluded that simvastatin disrupts cytoskeleton integrity and focal adhesion complex assembly in cultured cardiac fibroblasts by a cholesterol-independent mechanism and consequently decreases cell migration, adhesion and viability.
AB - Statins reduce the isoprenoids farnesyl and geranylgeranyl pyrophosphate, essential intermediates, which control a diversity of cellular events such as cytoskeleton integrity, adhesion, migration and viability. Cardiac fibroblasts are the major non-myocyte cell constituent in the normal heart, and play a key role in the maintenance of extracellular matrix. The effects of simvastatin on cardiac fibroblast processes previously mentioned remain unknown. Our aims were to investigate the effects of simvastatin on cytoskeleton structure and focal adhesion complex assembly and their relationships with cell adhesion, migration and viability in cultured cardiac fibroblasts. To this end, cells were treated with simvastatin for 24. h and changes in actin cytoskeleton, levels of vimentin and paxillin as well as their subcellular localization were analyzed by Western blot and immunocytochemistry, respectively. Cell adhesion to plastic or collagen coated dishes, migration in Transwell chambers, and cell viability were analyzed after simvastatin treatment. Our results show that simvastatin disrupts actin cytoskeleton and focal adhesion complex evaluated by phalloidin stain and immunocytochemistry for paxillin and vinculin. All these effects occurred by a cholesterol synthesis-independent mechanism. Simvastatin decreased cell adhesion, migration and viability in a concentration-dependent manner. Finally, simvastatin decreased angiotensin II-induced phospho-paxillin levels and cell adhesion. We concluded that simvastatin disrupts cytoskeleton integrity and focal adhesion complex assembly in cultured cardiac fibroblasts by a cholesterol-independent mechanism and consequently decreases cell migration, adhesion and viability.
KW - Cardiac fibroblast
KW - Cytoskeleton
KW - Focal adhesion complex
KW - Migration
KW - Simvastatin
UR - http://www.scopus.com/inward/record.url?scp=84857796500&partnerID=8YFLogxK
U2 - 10.1016/j.tox.2012.01.011
DO - 10.1016/j.tox.2012.01.011
M3 - Article
C2 - 22306966
AN - SCOPUS:84857796500
SN - 0300-483X
VL - 294
SP - 42
EP - 49
JO - Toxicology
JF - Toxicology
IS - 1
ER -