Disruption of Stromal-Derived Factor-1/Chemokine Receptor 4 by Simvastatin

Background: The alpha chemokine, stromal-derived factor (SDF)-1 is produced by bone marrow stromal cells
and other cells, especially damaged tissues. SDF-1 receptor, a chemokine receptor 4 (CXCR4), is expressed
on inflammatory cells and that SDF-1/CXCR4 axis plays a critical role in migration of inflammatory cells. In
cardiovascular diseases, SDF-1 is produced by endothelial cells and plaques and that SDF-1 chemoattracts
monocytes to the endothelial cells resulting in a local inflammation. Simvastatin, a cholesterol-lowering agent,
is a general drug for treatment of cardiovascular diseases. However, its molecular mechanism has not yet been
completely elucidated.
Method: Herein, we investigated the role of simvastatin on the SDF- 1/CXCR4 axis by employing flow cytometry,
RT-PCR, chemotaxis and adhesion assays.
Results: Simvastatin (i) downregulates CXCR4 expression on monocytic cell line (THP-1) and primary monocyte
in a dose-dependent manner, (ii) inhibits adhesion of monocytes to endothelial cells and (iii) decreases
SDF-1 production by endothelial cells. Moreover, preincubation with simvastatin significantly decreased the
migration of THP-1 towards the SDF-1 gradient.
Conclusion: All together our data indicate that simvastatin inhibits the binding of monocytes to endothelial cells
through disrupting of the SDF-1/CXCR4 axis.