Simvastatin disrupts cytoskeleton and decreases cardiac fibroblast adhesion, migration and viability.
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.
Centro Estudios Moleculares de la Célula, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
Miguel
M
Copaja
Daniel
D
Venegas
Pablo
P
Aranguiz
Jimena
J
Canales
Raul
R
Vivar
Yennifer
Y
Avalos
Lorena
L
Garcia
Mario
M
Chiong
Ivonne
I
Olmedo
Mabel
M
Catalán
Lisette
L
Leyton
Sergio
S
Lavandero
Guillermo
G
Díaz-Araya
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D058628:Myofibroblasts / Q000187:drug effects* / Q000502:physiology; D051419:Paxillin / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D013729:Terpenes / Q000494:pharmacology; D016596:Vinculin / Q000187:drug effects
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051419:Paxillin; D013729:Terpenes; D016596:Vinculin; D019821:Simvastatin