title: Statin-induced expression of decay-accelerating factor protects vascular endothelium against complement-mediated injury.
abstract: Complement-mediated vascular injury is important in the pathophysiology of atherosclerosis and myocardial infarction. Because recent evidence shows that statins have beneficial effects on endothelial cell (EC) function independent of lipid lowering, we explored the hypothesis that statins modulate vascular EC resistance to complement through the upregulation of complement-inhibitory proteins. Human umbilical vein and aortic ECs were treated with atorvastatin or simvastatin, and decay-accelerating factor (DAF), membrane cofactor protein, and CD59 expression was measured by flow cytometry. A dose-dependent increase in DAF expression of up to 4-fold was seen 24 to 48 hours after treatment. Statin-induced upregulation of DAF required increased steady-state mRNA and de novo protein synthesis. L-Mevalonate and geranylgeranyl pyrophosphate reversed the effect, confirming the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition and suggesting that constitutive DAF expression is negatively regulated by geranylgeranylation. Neither farnesyl pyrophosphate nor squalene inhibited statin-induced DAF expression, suggesting that the effect is independent of cholesterol lowering. Statin-induced DAF upregulation was mediated by the activation of protein kinase Calpha and inhibition of RhoA and was independent of phosphatidylinositol-3 kinase and NO activity. The increased DAF expression was functionally effective, resulting in significant reduction of C3 deposition and complement-mediated lysis of antibody-coated ECs. These observations provide evidence for a novel cytoprotective action of statins on vascular endothelium that is independent of the effect on lipids and results in enhanced protection against complement-mediated injury. Modulation of complement regulatory protein expression may contribute to the early beneficial effects of statins in reducing the morbidity and mortality associated with atherosclerosis.
authors.affiliation: British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College, Hammersmith Hospital, London, UK. justin.mason@ic.ac.uk
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
authors.forename: Zahra
authors.initials: Z
authors.lastname: Ahmed
authors.forename: Rivka
authors.initials: R
authors.lastname: Mankoff
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Lidington
authors.forename: Saifur
authors.initials: S
authors.lastname: Ahmad
authors.forename: Vinay
authors.initials: V
authors.lastname: Bhatia
authors.forename: Anne
authors.initials: A
authors.lastname: Kinderlerer
authors.forename: Anna M
authors.initials: AM
authors.lastname: Randi
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
mesh_terms: D000069059:Atorvastatin; D018958:CD55 Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D003167:Complement Activation; D003176:Complement C3 / Q000378:metabolism; D019610:Cytoprotection; D004224:Diterpenes / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006538:Heptanoic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D019821:Simvastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000502:physiology
chemical_list: D018958:CD55 Antigens; D003176:Complement C3; D004224:Diterpenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D012333:RNA, Messenger; D009569:Nitric Oxide; D000069059:Atorvastatin; D019821:Simvastatin; C017338:geranylgeraniol; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020741:rho GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid