Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis.
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.
Ueland
Thor
T
Research Institute for Internal Medicine, Rikshospitalet, Oslo University Hospital, N-0027 Oslo, Norway. thor.ueland@medisin.uio.no
Otterdal
Kari
K
Lekva
Tove
T
Halvorsen
Bente
B
Gabrielsen
Anders
A
Sandberg
Wiggo J
WJ
Paulsson-Berne
Gabrielle
G
Pedersen
Turid M
TM
Folkersen
Lasse
L
Gullestad
Lars
L
Oie
Erik
E
Hansson
Göran K
GK
Aukrust
Pål
P
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
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins