title: Cerivastatin reduces cytokine-induced surface expression of ICAM-1 via increased shedding in human endothelial cells.
abstract: Activation of endothelial cells is an incipient process in atherogenesis and leads to induction of the cellular adhesion molecules ICAM-1 and VCAM-1. Their expression can be induced by cytokines as well as other inflammatory mediators. The effects of HMG-CoA reductase inhibitors (statins) include mediation of anti-inflammatory properties. The aim of this study was the comparison of cerivastatin and simvastatin-mediated effects on inflammation-induced ICAM-1 and VCAM-1 expression in human umbilical venous endothelial cells (HUVEC). In HUVEC, TNF-alpha induced ICAM-1 and VCAM-1 mRNA and surface expression. Co-incubation with cerivastatin, but not simvastatin reduced TNF-alpha-induced up-regulation of ICAM-1 surface expression whereas both statins reduced VCAM-1 surface expression; all reductions in surface expression correlated with an increase in the soluble forms of ICAM-1 and VCAM-1 in cell culture supernatants. Mevalonate and nonsteroidal isoprenoids significantly reversed protein expression and shedding. Both statins caused an aggravation of TNF-alpha-induced ICAM-1 and VCAM-1 mRNA expression which was dependent on RNA synthesis. The statin-mediated increase in ICAM-1 and VCAM-1 mRNA expression correlated with the degradation of IkappaBa. Nuclear translocation of p65 was not significantly affected by statin-treatment of cytokine-treated cells. We conclude that cerivastatin and simvastatin reduce TNF-alpha-induced up-regulation of ICAM-1 and VCAM-1 surface expression via increased protein shedding mediated by HMG-CoA reductase inhibition and subsequent isoprenoid depletion.
authors.affiliation: Department of Internal Medicine B, Ernst Moritz Arndt University, Friedrich-Loeffler-Strasse 23 a, 17487 Greifswald, Germany. martin.landsberger@uni-greifswald.de
authors.forename: Martin
authors.initials: M
authors.lastname: Landsberger
authors.forename: Birger
authors.initials: B
authors.lastname: Wolff
authors.forename: Franziska
authors.initials: F
authors.lastname: Jantzen
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenstengel
authors.forename: Dirk
authors.initials: D
authors.lastname: Vogelgesang
authors.forename: Alexander
authors.initials: A
authors.lastname: Staudt
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Dahm
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
mesh_terms: D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D014657:Vasculitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020672:I-kappa B Proteins; D008565:Membrane Proteins; C000606204:NFKBIA protein, human; D019384:Nucleic Acid Synthesis Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D003609:Dactinomycin; D019821:Simvastatin; C086276:cerivastatin