title: Simvastatin alters human endothelial cell adhesion molecule expression and inhibits leukocyte adhesion under flow.
abstract: Hypercholesterolaemia is implicated as an independent risk factor in the pathogenesis of atherosclerosis. HMG-CoA reductase inhibitors (statins) are prescribed for their lipid-lowering effects but recent evidence suggests they have pleiotropic effects independent of lipid balance regulation that may explain their role in dramatically decreasing cardiovascular mortality and morbidity. The mechanisms responsible are unclear but endothelial cell (EC) dysfunction is critical. To investigate potential anti-inflammatory properties of statins on EC, functional responses of human umbilical vein endothelial cells (HUVEC) and human neutrophils under physiological flow conditions were studied. These interactions were quantified in response to inflammatory mediators following pre-treatment with statin. Histamine stimulation resulted in significant (p<0.001) increases in transient interactions between neutrophils and EC (tethering). These effects were significantly reduced (p<0.001) on pre-treatment with statin. TNF-alpha stimulation resulted in significant (p<0.001) increases in rolling interactions. These effects were significantly (p<0.001) reduced following pre-treatment of EC with statin. Mevalonate pre-treatment of EC significantly reversed the effects of statin pre-treatment on both tethering and rolling (p<0.001). Reductions in surface expression of P- and E-selectin were confirmed by ELISA. EC exposed to histamine demonstrated significantly increased (p<0.01) levels of P-selectin, abrogated (p<0.001) by pre-treatment with statin. EC exposed to TNF-alpha demonstrated a significant increase (p<0.001) in levels of E-selectin, reduced (p<0.05) by pre-treatment with statin.
authors.affiliation: Centre for Atherothrombosis Research, Bradford University, BD7 1DP, United Kingdom. K.Eccles@bradford.ac.uk
authors.forename: Kirstie A
authors.initials: KA
authors.lastname: Eccles
authors.forename: Heather
authors.initials: H
authors.lastname: Sowden
authors.forename: Karen E
authors.initials: KE
authors.lastname: Porter
authors.forename: Sue M
authors.initials: SM
authors.lastname: Parkin
authors.forename: Shervanthi
authors.initials: S
authors.lastname: Homer-Vanniasinkam
authors.forename: Anne M
authors.initials: AM
authors.lastname: Graham
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D019040:E-Selectin / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D036904:Leukocyte Rolling / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects; D019007:P-Selectin / Q000187:drug effects*; D012212:Rheology; D019821:Simvastatin / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D019040:E-Selectin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019007:P-Selectin; D019821:Simvastatin