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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1228.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

Dickkopf-1 Enhances Inflammatory Interaction Between Platelets and Endothelial Cells and Shows Increased Expression in Atherosclerosis

Thor Ueland; Kari Otterdal; Tove Lekva; Bente Halvorsen; Anders Gabrielsen; Wiggo J. Sandberg; Gabrielle Paulsson-Berne; Turid M. Pedersen; Lasse Folkersen; Lars Gullestad; Erik Øie; Göran K. Hansson; Pål Aukrust

From the Research Institute for Internal Medicine (T.U., K.O., T.L., B.H., W.J.S., T.M.P., E.O., P.A.), the Department of Endocrinology (T.U., T.L.), the Department of Cardiology (L.G., E.O.), and the Section of Clinical Immunology and Infectious Diseases (P.A.), Rikshospitalet, Oslo University Hospital, and the Faculty of Medicine (T.U., K.O., B.H., L.G., P.A.), University of Oslo, Norway; and the Centre for Molecular Medicine (A.G., G.P.-B., L.F., G.K.H.), Karolinska Institute, Stockholm, Sweden.

Correspondence to Thor Ueland, Research Institute for Internal Medicine, Rikshospitalet, Oslo University Hospital, N-0027 Oslo, Norway. E-mail thor.ueland{at}medisin.uio.no

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.

Methods and 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/β-catenin pathway and activation of nuclear factor B.

Conclusion— 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.

We report increased levels of Dickkopf-1, a regulatory molecule of the wingless pathway, in experimental and clinical atherosclerosis, both systemically and within the plaques. Both endothelial- and platelet-derived Dickkopf-1 enhanced the inflammatory interaction between platelets and endothelial cells, potentially representing a self-perpetuating pathogenic mechanism in atherogenesis and plaque destabilization.

Key Words: atherosclerosis • endothelium • inflammation • platelets