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.

Simvastatin impairs murine melanoma growth

Statins induces cell cycle arrest, apoptosis, reduction of angiogenic factors, inhibition of theendothelial growth factor, impairing tissue adhesion and attenuation of the resistance mechanisms. The aim of thisstudy was evaluate the anti-tumoral activity of simvastatin in a B16F10 melanoma-mouse model.Melanoma cells were treated with different concentrations of simvastatin and assessed by viabilitymethods. Melanoma cells (5 ~ 104) were implanted in two month old C57Bl6/J mice. Around 7 days after cellsinjection, the oral treatments were started with simvastatin (5 mg/kg/day, p.o.). Tumor size, hematological andbiochemical analyses were evaluated.Simvastatin at a concentration of 0.8 ƒÊM, 1.2 ƒÊM and 1.6 ƒÊM had toxic effect. Concentration of 1.6 ƒÊMinduced a massive death in the first 24 h of incubation. Simvastatin at 0.8 ƒÊM induces early cell cycle arrest in G0/G1, followed by increase of hypodiploidy. Tumor size were evaluated and the difference of treated group andcontrol, after ten days, demonstrates that simvastatin inhibited the tumor expansion in 68%.Simvastatin at 1.6 ƒÊM, presented cytototoxicity after 72 h of treatment, with an intense death. In vivo,simvastatin being potentially useful as an antiproliferative drug, with an impairment of growth after ten days.

Effects of Simvastatin and L-arginine on vasodilation, nitric oxide metabolics and endogenous NOS Inhibitors in hypercholesterolemic subjects

The statins have lipid-lowering and pleiotropic properties, which could exert protective effects on the endothelium in hypercholesterolemia. The association of L-arginine with simvastatin could promote a further improvement on endothelial function in this condition. Thus, we investigated whether simvastatin, with or without supplementation with L-arginine, could improve endothelium-dependent vasodilation. In this study, 25 hypercholesterolemic subjects were treated according to the following protocol: washout period of 1 month; simvastatin (20 mg/day) for 2 months; simvastatin (20 mg/day) þ L-arginine (7 g/day) for 2 months. From these patients, 10 were chosen at random for evaluation of vascular function by high resolution ultrassonography of the brachial artery. In subjects treated with simvastatin plus L-arginine, an increase of L-arginine levels (68%) and L-arginine/asymmetric dimethylarginine (ADMA) ratio (67%) were observed. Simvastatin reduced the plasma concentrations of NO metabolites nitrite þ nitrate (NOx: 34%), S-nitrosothiols (RSNO: 42%), total cholesterol (25%),low density lipoprotein (LDL)-cholesterol (36%) and the LDL-cholesterol/high density lipoprotein (HDL)-cholesterol ratio (34%). Simvastatin, associated or not to L-arginine, did not affect ADMA levels and endotheliumdependent vasodilation. Our data showed that simvastatin reduced the plasma concentrations of NOx and RSNO without affecting either the levels of ADMA or endothelium- dependent vasodilation in hypercholesterolemia...