title: Laminar shear stress prevents simvastatin-induced adhesion molecule expression in cytokine activated endothelial cells.
abstract: In addition to lowering cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been shown to modulate gene expression in endothelial cells. The effect of statins on cell adhesion molecule expression is unclear and largely unexplored in endothelial cells exposed to shear stress, an important regulator of endothelial cell function. In this study, the effect of simvastatin on vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression was evaluated in human abdominal aortic endothelial cells (HAAEC) conditioned with various levels of laminar wall shear stress with or without tumor necrosis factor alpha (TNFα). As expected, TNFα alone greatly enhanced both VCAM-1 and ICAM-1 mRNA and protein. In static culture, simvastatin potentiated the TNFα-induced increase in VCAM-1 and ICAM-1 mRNA but not total protein at 24 h. Mevalonate, a precursor to cholesterol biosynthesis, eliminated the effect of simvastatin. Exposure of endothelial cells to elevated levels of laminar shear stress during simvastatin treatment prevented the potentiating effect of simvastatin on cell adhesion molecule mRNA. A shear stress of 12.5 dyn/cm² eliminated the increase in VCAM-1 by simvastatin, while 25 dyn/cm² was needed for ICAM-1. We conclude that simvastatin enhances VCAM-1 and ICAM-1 gene expression in TNFα-activated endothelial cells through inhibition of HMG-CoA reductase. High levels of laminar shear stress prevented the upregulation of VCAM-1 and ICAM-1 by simvastatin suggesting that an induction of cell adhesion molecules by statins may not occur in endothelial cells exposed to shear stress from blood flow.
authors.affiliation: Dept. of Chemical Engineering, McGill University, 3610 University Street, Montreal. Qc, H3A 2B2, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Rossi
authors.forename: Leonie
authors.initials: L
authors.lastname: Rouleau
authors.forename: Alexander
authors.initials: A
authors.lastname: Emmott
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Richard L
authors.initials: RL
authors.lastname: Leask
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology; D009994:Osmolar Concentration; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D015815:Cell Adhesion Molecules; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019821:Simvastatin; D008798:Mevalonic Acid