Atorvastatin preserves the integrity of endothelial adherens junctions by inhibiting vascular endothelial cadherin tyrosine phosphorylation.
Vascular endothelial cadherin (VE-cad) tyrosine (Tyr) phosphorylation has been implicated in the disruption of adherens junctions (AJs) induced by inflammatory reactions. The impacts of statins on integrity of AJs and VE-cad Tyr phosphorylation have not been explored. The effects of atorvastatin on IL-1β and monocyte-induced VE-cad Tyr phosphorylation in human umbilical vein endothelial cells (ECs) were studied. In ECs treated with interleukin (IL)-1β for 30 min, VE-cad Tyr phosphorylation, dissociation of the VE-cad/β-catenin complex and transendothelial migration (TEM) of monocytes were increased. These processes were mediated by activation of HRas and RhoA that leads to phosphorylation of myosin light chain (MLC). Atorvastatin inhibited IL-1β-induced Tyr phosphorylation of VE-cad by inhibiting RhoA and by dephosphorylating MLC. The attenuating effect of atorvastatin on VE-cad Tyr phosphorylation was reversed when RhoA was activated or MLC phosphatase was inhibited. Furthermore, inhibiting farnesyl transferase or geranylgeranyl transferase reproduced the inhibitory effects of atorvastatin on VE-cad Tyr phosphorylation. In addition, atorvastatin inhibited monocyte-induced VE-cad Tyr phosphorylation in ECs and attenuated IL-1β-induced TEM of monocytes. Our study introduces a novel pleiotropic effect of atorvastatin and suggests that statins protect the integrity of AJs in ECs by inhibiting RhoA-mediated Tyr phosphorylation of VE-cad.
Department of Internal Medicine, Division of Cardiology, The University of Texas Medical School at Houston, Houston, Texas, USA. mehran.haidari@uth.tmc.edu
Mehran
M
Haidari
Wei
W
Zhang
Zhenping
Z
Chen
Leila
L
Ganjehei
Ahmadreza
A
Mortazavi
Navin
N
Warier
Peter
P
Vanderslice
Richard A F
RA
Dixon
D022005:Adherens Junctions / Q000187:drug effects*; D000069059:Atorvastatin; D015820:Cadherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D018994:Myosin Light Chains / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000037:antagonists & inhibitors* / Q000378:metabolism
D015820:Cadherins; D006538:Heptanoic Acids; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D018994:Myosin Light Chains; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D000069059:Atorvastatin