Dataset Information

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

ABSTRACT:

Background

Dickkopf-3 (DKK3) is a negative regulator of the Wnt/?-catenin signaling pathway, which is involved in inflammation. However, little is known about the relationship between DKK3 expression and the progression of atherosclerosis. The aim of the present study was to define the role of DKK3 and its potential mechanism in the development of atherosclerosis.

Methods and results

Immunofluorescence analysis showed that DKK3 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. DKK3^-/-ApoE^-/- mice exhibited a significant decrease in atherosclerotic lesions in the entire aorta, aortic sinus, and brachiocephalic arteries. Transplantation of bone marrow from DKK3^-/-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 DKK3 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 DKK3^-/-ApoE^-/- mice. Furthermore, multiple proinflammatory cytokines exhibited marked decreases in DKK3^-/-ApoE^-/- mice. Finally, we observed that DKK3 ablation increased ?-catenin expression in the nuclei of macrophages both in vivo and in vitro.

Conclusions

DKK3 expression in macrophages is involved in the pathogenesis of atherosclerosis through modulation of inflammation and inactivation of the Wnt/?-catenin pathway.

SUBMITTER: Cheng WL

PROVIDER: S-EPMC5523766 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Cheng Wen-Lin WL Yang Yang Y Zhang Xiao-Jing XJ Guo Junhong J Gong Jun J Gong Fu-Han FH She Zhi-Gang ZG Huang Zan Z Xia Hao H Li Hongliang H

Journal of the American Heart Association 20170220 2

<h4>Background</h4>Dickkopf-3 (DKK3) is a negative regulator of the Wnt/β-catenin signaling pathway, which is involved in inflammation. However, little is known about the relationship between DKK3 expression and the progression of atherosclerosis. The aim of the present study was to define the role of DKK3 and its potential mechanism in the development of atherosclerosis.<h4>Methods and results</h4>Immunofluorescence analysis showed that DKK3 was strongly expressed in macrophages of atherosclero ...[more]

PMID: 28219919

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Project description:Atherogenesis is a long-term process that involves inflammatory response coupled with metabolic dysfunction. Foam cell formation and macrophage inflammatory response are two key events in atherogenesis. Adipocyte enhancer-binding protein 1 (AEBP1) has been shown to impede macrophage cholesterol efflux, promoting foam cell formation, via peroxisome proliferator-activated receptor (PPAR)-γ1 and liver X receptor α (LXRα) downregulation. Moreover, AEBP1 has been shown to promote macrophage inflammatory responsiveness by inducing nuclear factor (NF)-κB activity via IκBα downregulation. Lipopolysaccharide (LPS)-induced suppression of pivotal macrophage cholesterol efflux mediators, leading to foam cell formation, has been shown to be mediated by AEBP1. Herein, we showed that AEBP1-transgenic mice (AEBP1(TG)) with macrophage-specific AEBP1 overexpression exhibit hyperlipidemia and develop atherosclerotic lesions in their proximal aortas. Consistently, ablation of AEBP1 results in significant attenuation of atherosclerosis (males: 3.2-fold, P = 0.001 [en face]), 2.7-fold, P = 0.0004 [aortic roots]; females: 2.1-fold, P = 0.0026 [en face], 1.7-fold, P = 0.0126 [aortic roots]) in the AEBP1(-/-)/low-density lipoprotein receptor (LDLR )(-/-) double-knockout (KO) mice. Bone marrow (BM) transplantation experiments further revealed that LDLR (-/-) mice reconstituted with AEBP1(-/-)/LDLR (-/-) BM cells (LDLR (-/-)/KO-BM chimera) display significant reduction of atherosclerosis lesions (en face: 2.0-fold, P = 0.0268; aortic roots: 1.7-fold, P = 0.05) compared with control mice reconstituted with AEBP1(+/+)/LDLR (-/-) BM cells (LDLR (-/-)/WT-BM chimera). Furthermore, transplantation of AEBP1(TG) BM cells with the normal apolipoprotein E (ApoE) gene into ApoE (-/-) mice (ApoE (-/-)/TG-BM chimera) leads to significant development of atherosclerosis (males: 2.5-fold, P = 0.0001 [en face], 4.7-fold, P = 0.0001 [aortic roots]; females: 1.8-fold, P = 0.0001 [en face], 3.0-fold, P = 0.0001 [aortic roots]) despite the restoration of ApoE expression. Macrophages from ApoE (-/-)/TG-BM chimeric mice express reduced levels of PPARγ1, LXRα, ATP-binding cassette A1 (ABCA1) and ATP-binding cassette G1 (ABCG1) and increased levels of the inflammatory mediators interleukin (IL)-6 and tumor necrosis factor (TNF)-α compared with macrophages of control chimeric mice (ApoE (-/-)/NT-BM ) that received AEBP1 nontransgenic (AEBP1(NT) ) BM cells. Our in vivo experimental data strongly suggest that macrophage AEBP1 plays critical regulatory roles in atherogenesis, and it may serve as a potential therapeutic target for the prevention or treatment of atherosclerosis.

Dataset Information

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

Background

Methods and results

Conclusions

Publications

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

Similar Datasets

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