Dickkopf‐3 Ablation Attenuates the Development of Atherosclerosis in ApoE‐Deficient Mice

Abstract

Background Dickkopf‐3 ( DKK 3) is a negative regulator of the Wnt/β‐catenin signaling pathway, which is involved in inflammation. However, little is known about the relationship between DKK 3 expression and the progression of atherosclerosis. The aim of the present study was to define the role of DKK 3 and its potential mechanism in the development of atherosclerosis. Methods and Results Immunofluorescence analysis showed that DKK 3 was strongly expressed in macrophages of atherosclerotic plaques from patients with coronary heart disease and in hyperlipidemic mice. The expression level was significantly increased in atherogenesis. DKK 3 −/− ApoE −/− mice exhibited a significant decrease in atherosclerotic lesions in the entire aorta, aortic sinus, and brachiocephalic arteries. Transplantation of bone marrow from DKK 3 −/− ApoE −/− mice into lethally irradiated ApoE −/− recipients resulted in a reduction of atherosclerotic lesions, compared with the lesions in recipients transplanted with ApoE −/− donor cells, suggesting that the effect of DKK 3 deficiency was largely mediated by bone marrow–derived cells. A reduction in the necrotic core size, accompanied by increased collagen content and smooth muscle cells and decreased accumulation of macrophages and lipids, contributed to the stability of plaques in DKK 3 −/− ApoE −/− mice. Furthermore, multiple proinflammatory cytokines exhibited marked decreases in DKK 3 −/− ApoE −/− mice. Finally, we observed that DKK 3 ablation increased β‐catenin expression in the nuclei of macrophages both in vivo and in vitro. Conclusions DKK 3 expression in macrophages is involved in the pathogenesis of atherosclerosis through modulation of inflammation and inactivation of the Wnt/β‐catenin pathway.