HMG-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro - Involvement of Rho GTPase-dependent mechanism

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, hav e been reported to exert actions independent of their lipid-lowering effect s. To critically assess the effects of statins on monocyte-endothelial cell interactions, we used an in vitro model that mimicked physiological flow c onditions. Monocytic U937 cells were incubated in the presence of cerivasta tin for 48 hours. Adhesive interactions of statin-treated U937 cells were t hen analyzed by use of activated (interleukin-1 beta 10 U/mL, 4 hours) huma n umbilical vein endothelial cells in an in vitro flow apparatus. Flow cyto metric analysis of adhesion molecules and measurement of F-actin content in U937 cells were performed before and after statin treatment. Preincubation with cerivastatin significantly decreased U937 firm adhesion to activated human umbilical vein endothelial cells, whereas U937 rolling was not decrea sed. Fluorescence-activated cell sorter analysis revealed downregulation of U937 surface expression of CD11a, CD18, and VLA4 after statin treatment. C erivastatin significantly reduced F-actin content in U937 cells and inhibit ed RhoA translocation, whereas preincubation with C3 exoenzyme reduced U937 adhesion under flow. Cerivastatin reduces monocyte adhesion to vascular en dothelium under physiological flow conditions via downregulation of integri n adhesion molecules and inhibition of actin polymerization via RhoA inacti vation. Our findings have important implications for the lipid-independent effects of statins.