A Cytokine-Like Protein Dickkopf-Related Protein 3 Is Atheroprotective

TY - JOUR

T1 - A Cytokine-Like Protein Dickkopf-Related Protein 3 Is Atheroprotective

AU - Yu, Baoqi

AU - Kiechl, Stefan

AU - Qi, Dan

AU - Wang, Xiaocong

AU - Song, Yanting

AU - Weger, Siegfried

AU - Mayr, Agnes

AU - Le Bras, Alexandra

AU - Karamariti, Eirini

AU - Zhang, Zhongyi

AU - del Barco Barrantes, Ivan

AU - Niehrs, Christof

AU - Schett, Georg

AU - Hu, Yanhua

AU - Wang, Wen

AU - Willeit, Johann

AU - Qu, Aijuan

AU - Xu, Qingbo

PY - 2017/9/12

Y1 - 2017/9/12

N2 - BACKGROUND—: Dickkopf-related protein (DKK) 3 is a secreted protein that is involved in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but little is known about its role in atherosclerosis. METHODS—: We tested the hypothesis that DKK3 is atheroprotective using both epidemiological and experimental approaches. Blood DKK3 levels were measured in the Bruneck Study in 2000 (n=684) and then in 2005 (n=574). DKK3-deficient mice were crossed to ApoE mice to evaluate atherosclerosis development and vessel injury-induced neointimal formation. Endothelial cell migration and the underlying mechanisms were studied using in vitro cell culture models. RESULTS—: In the prospective population-based Bruneck Study, the level of plasma DKK3 was inversely related to carotid artery intima-media thickness and five-year progression of carotid atherosclerosis, independently from standard risk factors for atherosclerosis. Experimentally, we analyzed the area of atherosclerotic lesions, femoral artery injury-induced re-endothelialization and neointima formation in both DKK3/ApoE and DKK3/ApoE mice. It was demonstrated that DKK3 deficiency accelerated atherosclerosis and delayed re-endothelialization with consequently exacerbated neointima formation. To explore the underlying mechanisms, we performed transwell and scratch migration assays using cultured human endothelial cells, which exhibited a significant induction in cell migration in response to DKK3 stimulation. This DKK3-induced migration was associated with activation of ROR2 and DVL1, activated Rac1 GTPases and upregulated JNK and c-jun phosphorylation in endothelial cells. Knockdown of ROR2 receptor using specific siRNA or transfection of a dominant negative form of Rac1 in endothelial cells markedly inhibited cell migration and downstream JNK and c-jun phosphorylation. CONCLUSIONS—: This study provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair, with great therapeutic potential implications against atherosclerosis.Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

AB - BACKGROUND—: Dickkopf-related protein (DKK) 3 is a secreted protein that is involved in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but little is known about its role in atherosclerosis. METHODS—: We tested the hypothesis that DKK3 is atheroprotective using both epidemiological and experimental approaches. Blood DKK3 levels were measured in the Bruneck Study in 2000 (n=684) and then in 2005 (n=574). DKK3-deficient mice were crossed to ApoE mice to evaluate atherosclerosis development and vessel injury-induced neointimal formation. Endothelial cell migration and the underlying mechanisms were studied using in vitro cell culture models. RESULTS—: In the prospective population-based Bruneck Study, the level of plasma DKK3 was inversely related to carotid artery intima-media thickness and five-year progression of carotid atherosclerosis, independently from standard risk factors for atherosclerosis. Experimentally, we analyzed the area of atherosclerotic lesions, femoral artery injury-induced re-endothelialization and neointima formation in both DKK3/ApoE and DKK3/ApoE mice. It was demonstrated that DKK3 deficiency accelerated atherosclerosis and delayed re-endothelialization with consequently exacerbated neointima formation. To explore the underlying mechanisms, we performed transwell and scratch migration assays using cultured human endothelial cells, which exhibited a significant induction in cell migration in response to DKK3 stimulation. This DKK3-induced migration was associated with activation of ROR2 and DVL1, activated Rac1 GTPases and upregulated JNK and c-jun phosphorylation in endothelial cells. Knockdown of ROR2 receptor using specific siRNA or transfection of a dominant negative form of Rac1 in endothelial cells markedly inhibited cell migration and downstream JNK and c-jun phosphorylation. CONCLUSIONS—: This study provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair, with great therapeutic potential implications against atherosclerosis.Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

UR - http://www.scopus.com/inward/record.url?scp=85022064005&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.117.027690

DO - 10.1161/CIRCULATIONAHA.117.027690

M3 - Article

AN - SCOPUS:85022064005

SN - 0009-7322

VL - 136

SP - 1022

EP - 1036

JO - Circulation (Baltimore)

JF - Circulation (Baltimore)

IS - 11

ER -