title: Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis.
abstract: OBJECTIVE
  Based on the emerging importance of the wingless (Wnt) pathways in inflammation and vascular biology, we hypothesized a role for Dickkopf-1 (DKK-1), a major modulator of Wnt signaling, in atherogenesis and plaque destabilization.
  
  
  RESULTS
  We report increased levels of DKK-1 in experimental (ApoE(-/-) mice) and clinical (patients with coronary artery disease [n=80] and patients with carotid plaque [n=47]) atherosclerosis, both systemically (serum) and within the lesion, with particularly high levels in advanced and unstable disease. We identified platelets as an important cellular source of DKK-1 as shown by in vitro experiments and by immunostaining of thrombus material obtained at the site of plaque rupture in patients with acute ST-elevation myocardial infarction, with strong immunoreactivity in platelet aggregates. Our in vitro experiments identified a role for platelet- and endothelial-derived DKK-1 in platelet-dependent endothelial activation, promoting enhanced release of inflammatory cytokines. These inflammatory effects of DKK-1 involved inhibition of the Wnt/beta-catenin pathway and activation of nuclear factor kappaB.
  
  
  CONCLUSIONS
  Our findings identify DKK-1 as a novel mediator in platelet-mediated endothelial cell activation. The demonstration of enhanced DKK-1 expression within advanced carotid plaques may suggest that this DKK-1-driven inflammatory loop could be operating within the atherosclerotic lesion.
authors.affiliation: Research Institute for Internal Medicine, Rikshospitalet, Oslo University Hospital, N-0027 Oslo, Norway. thor.ueland@medisin.uio.no
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Kari
authors.initials: K
authors.lastname: Otterdal
authors.forename: Tove
authors.initials: T
authors.lastname: Lekva
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Anders
authors.initials: A
authors.lastname: Gabrielsen
authors.forename: Wiggo J
authors.initials: WJ
authors.lastname: Sandberg
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Paulsson-Berne
authors.forename: Turid M
authors.initials: TM
authors.lastname: Pedersen
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.forename: Erik
authors.initials: E
authors.lastname: Oie
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D011379:Prognosis
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins