Abstract 16242: Atorvastatin Preserves the Integrity of Adherens Junctions in Endothelial Cells
Endothelial barrier function depends on the integrity of intercellular adherens junctions formed by the complex between VE-cadherin (VE-cad) and catenins. VE-cad tyrosine phosphorylation has been implicated in the impairment of endothelium barrier function and disruption of adherens junction. The effects of statins on stability of adherens junctions remain undetermined. Using a combination of biochemical and cellular techniques we tested this hypothesis that statins preserve the integrity of adherens junctions in endothelial cells (ECs) by inhibiting VE-cad tyrosine phosphorylation. The effects of atorvastatin on VE-cad tyrosine phosphorylation in human umbilical vein ECs were studied. In ECs treated with interleukin (IL)-1, VE-cad tyrosine phosphorylation and dissociation of the VE-cad/β-catenin complex were increased. These processes were mediated by RhoA, HRas, and phosphorylation of myosin light chain (MLC). We observed that atorvastatin and rosuvastatin inhibited basal and IL-1-induced tyrosine phosphorylation of VE-cad by inhibiting RhoA and HRas and by dephosphorylating MLC. Atorvastatin inhibits IL-1-induced disruption of the VE-cad/β-catenin complex. The attenuating effect of atorvastatin on IL-1-induced VE-cad tyrosine phosphorylation was partly reversed when MLC phosphatase was inhibited by using siRNA against MYPT or when constitutively active forms of HRas and RhoA were overexpressed in ECs. Furthermore, inhibiting farnesyl transferase or geranyl geranyl transferase reproduced the inhibitory effects of atorvastatin on VE-cad tyrosine phosphorylation, whereas the addition of farnesyl pyrophosphate or geranylgeranyl pyrophosphate reversed the inhibitory effects of atorvastatin on VE-cad tyrosine phosphorylation. In addition, atorvastatin inhibited monocyte-induced VE-cad tyrosine phosphorylation in ECs, independent of the expression of major adhesion molecules (eg, ICAM-1, VCAM-1, and E-selectin). Our study introduces a novel pleiotropic effect of atorvastatin and suggests that statins protect the integrity of adherens junctions in ECs by inhibiting VE-cad tyrosine phosphorylation.
- © 2011 by American Heart Association, Inc.