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

Abstract

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.