Simvastatin inhibits the migration and adhesion of monocytic cells and disorganizes the cytoskeleton of activated endothelial cells

• Published in: European journal of pharmacology Vol. 548; no. 1; pp. 53 - 63
• Main Authors: Pozo, Mayte, de Nicolás, Rosario, Egido, Jesús, González-Cabrero, Jesús
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 24.10.2006; Elsevier
• Subjects: Actins - drug effects; Actins - physiology; Adhesion molecule; Anticholesteremic Agents - pharmacology; Biological and medical sciences; Cell Adhesion - drug effects; Cell Line; Cell Movement - drug effects; Chemokine CCL2 - pharmacology; Chemotaxis; Cytoskeleton; Cytoskeleton - drug effects; Endothelial cell; Endothelial Cells - drug effects; Endothelial Cells - physiology; Humans; Interleukin-1beta - pharmacology; Medical sciences; Mevalonic Acid - pharmacology; Monocyte; Monocytes - drug effects; Monocytes - physiology; Pharmacology. Drug treatments; Polyisoprenyl Phosphates - pharmacology; Sesquiterpenes; Simvastatin - pharmacology; Statin; Cytoskeleton; Endothelial cell; Adhesion molecule; Statin; Monocyte; Chemotaxis; Enzyme; Simvastatin; Enzyme inhibitor; Statin derivative; Adhesion; In vitro; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; Antilipemic agent
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2006.08.003

Statins are powerful agents for lowering plasma cholesterol levels, which act by inhibition of the 3-hydroxy-3-methylglutaryl-CoA reductase. Evidence suggests that some of the beneficial effects may depend on their anti-inflammatory properties, due to their ability to suppress the synthesis of isoprenoids. The present study analyzes the effects of short-term simvastatin exposure on monocyte migration, cell adhesion, and endothelial cytoskeleton. We demonstrate that simvastatin completely inhibited the migration of THP-1 monocytic cells after 24 h of incubation, being prevented by coincubation with mevalonate (MVA) and geranylgeranylpyrophosphate (GGPP), but not by farnesylpyrophosphate (FPP). Simvastatin decreased chemotaxis to 70% after one hour of incubation; surprisingly neither MVA, GGPP nor FPP were able to restore the effects of the drug. Simvastatin also significantly reduced the adhesion of monocytes to interleukin-1β (IL-1β)-activated endothelium to 80% after preincubation for 24 h. This effect was completely reversed by coincubation with MVA and GGPP, and partially with FPP. Unexpectedly, simvastatin increased adhesion molecules expression VCAM-1 and ICAM-1 on cytokine-stimulated endothelial cells. Examination of the actin cytoskeleton on IL-1β-activated endothelial cells showed that both 4 and 24 h of incubation with simvastatin produced a complete disappearance of F-actin, being completely restored by MVA and partially by GGPP and FPP after 24 h of coincubation. We suggest that cytoskeleton disorganization in endothelial cells is important for inhibiting monocyte adhesion, altering the adhesion molecules function. Taken together, these results strongly support the beneficial anti-inflammatory properties of statins, contributing to the overall clinical effects.