title: Statin-induced expression of CD59 on vascular endothelium in hypoxia: a potential mechanism for the anti-inflammatory actions of statins in rheumatoid arthritis.
abstract: Hypoxia, which leads to dysfunctional cell metabolism, and complement activation both play central roles in the pathogenesis of rheumatoid arthritis (RA). Recent studies have reported that mice deficient for the complement-inhibitory protein CD59 show enhanced susceptibility to antigen-induced arthritis and reported that statins have anti-inflammatory effects in RA. We hypothesized that the anti-inflammatory effect of statins in RA relates in part to their ability to increase CD59 expression in hypoxic conditions and therefore to reduce complement activation. Flow-cytometric analysis showed that CD59 expression on endothelial cells (EC) was unaffected by atorvastatin in normoxia (21% O2), whereas in hypoxic conditions (1% O2) an up to threefold dose-dependent increase in CD59 expression was seen. This effect of hypoxia was confirmed by treatment of EC with chemical mimetics of hypoxia. The upregulation of CD59 protein expression in hypoxia was associated with an increase in steady-state mRNA. L-Mevalonate and geranylgeraniol reversed the response, confirming a role for inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and geranylgeranylation. Likewise, inhibition by NG-monomethyl-L-arginine and NG-nitro-L-arginine methyl ester confirmed that CD59 upregulation in hypoxia was nitric oxide dependent. The expression of another complement-inhibitory protein, decay-accelerating factor (DAF), is known to be increased by atorvastatin in normoxia; this response was also significantly enhanced under hypoxic conditions. The upregulation of CD59 and DAF by atorvastatin in hypoxia prevented the deposition of C3, C9 and cell lysis that follows exposure of reoxygenated EC to serum. This cytoprotective effect was abrogated by inhibitory anti-CD59 and anti-DAF mAbs. The modulation of EC CD59 and DAF by statins under hypoxic conditions therefore inhibits both early and late complement activation and may contribute to the anti-inflammatory effects of statins in RA.
authors.affiliation: Cardiovascular Medicine Unit, Eric Bywaters Center for Vascular Inflammation, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Kinderlerer
authors.forename: Rivka
authors.initials: R
authors.lastname: Steinberg
authors.forename: Michael
authors.initials: M
authors.lastname: Johns
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Harten
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Lidington
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D000069059:Atorvastatin; D018958:CD55 Antigens / Q000378:metabolism; D018957:CD59 Antigens / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D019610:Cytoprotection; D003676:Deferoxamine / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology*; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000860:Hypoxia / Q000276:immunology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D018958:CD55 Antigens; D018957:CD59 Antigens; D004224:Diterpenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007502:Iron Chelating Agents; D011758:Pyrroles; D012333:RNA, Messenger; D003035:Cobalt; D000069059:Atorvastatin; C017338:geranylgeraniol; C018021:cobaltous chloride; D003676:Deferoxamine; D008798:Mevalonic Acid