title: Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells.
abstract: BACKGROUND
  Although CD40 signaling participates in atherosclerosis, links between lipid risk factors and this inflammatory pathway remain obscure. Cardiovascular risk reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may involve actions beyond lipid lowering, including reduced inflammation. Therefore, this study analyzed whether oxidized low-density lipoprotein (oxLDL) induces CD40/CD40L expression on cells implicated in atherogenesis and whether statins affect their expression in vitro as well as the expression of soluble CD40L (sCD40L) in vivo.
  
  
  RESULTS
  Treatment of human vascular endothelial and smooth muscle cells and mononuclear phagocytes with oxLDL augmented the basal expression of CD40 and CD40L mRNA and protein. In contrast, cerivastatin, atorvastatin, or simvastatin concentration-dependently diminished the constitutive as well as oxLDL- or cytokine-induced expression of the receptor/ligand dyad, an effect reversed by mevalonate. Patients treated with statins had diminished sCD40L plasma levels compared with untreated control patients (8.3+/-3.1 ng/mL [n=11] versus 13.1+/-2.5 ng/mL [n=16], P<0.05), supporting the clinical relevance of the in vitro observations. Platelet-enriched plasma of mice deficient in CD40L showed markedly delayed fibrin clot formation, suggesting a role for the ligand in blood coagulation and supporting the hypothesis that statin-mediated reduction in CD40/CD40L expression might limit thrombosis.
  
  
  CONCLUSIONS
  OxLDL may promote expression of CD40 and CD40L in human atheroma. Statins may limit the expression of the CD40 receptor/ligand dyad in two ways, directly as well as through diminished lipoprotein levels. Thus, reduced CD40 signaling may account for some of the statins' antiinflammatory action.
authors.affiliation: Leducq Center for Cardiovascular Research, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA. uschoenbeck@rics.bwh.harvard.edu
authors.forename: Uwe
authors.initials: U
authors.lastname: Schönbeck
authors.forename: Norbert
authors.initials: N
authors.lastname: Gerdes
authors.forename: Nerea
authors.initials: N
authors.lastname: Varo
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Reynolds
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Horton
authors.forename: Udo
authors.initials: U
authors.lastname: Bavendiek
authors.forename: Linda
authors.initials: L
authors.lastname: Robbie
authors.forename: Peter
authors.initials: P
authors.lastname: Ganz
authors.forename: Scott
authors.initials: S
authors.lastname: Kinlay
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D001777:Blood Coagulation / Q000235:genetics; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015331:Cohort Studies; D023921:Coronary Stenosis / Q000097:blood / Q000188:drug therapy*; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010586:Phagocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D011725:Pyridines; D011758:Pyrroles; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D023201:CD40 Ligand; D000069059:Atorvastatin; D019821:Simvastatin; C086276:cerivastatin