DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells.

Abstract

OBJECTIVE:

DKK3 (dickkopf 3), a 36-kD secreted glycoprotein, has been shown to be involved in the differentiation of partially reprogrammed cells and embryonic stem cells to smooth muscle cells (SMCs), but little is known about its involvement in vascular disease. This study aims to assess the effects of DKK3 on atherosclerotic plaque composition.

APPROACH AND RESULTS:

In the present study, we used a murine model of atherosclerosis (ApoE-/-) in conjunction with DKK3-/- and performed tandem stenosis of the carotid artery to evaluate atherosclerotic plaque development. We found that the absence of DKK3 leads to vulnerable atherosclerotic plaques, because of a reduced number of SMCs and reduced matrix protein deposition, as well as increased hemorrhage and macrophage infiltration. Further in vitro studies revealed that DKK3 can induce differentiation of Sca1+ (stem cells antigen 1) vascular progenitors and fibroblasts into SMCs via activation of the TGF-β (transforming growth factor-β)/ATF6 (activating transcription factor 6) and Wnt signaling pathways. Finally, we assessed the therapeutic potential of DKK3 in mouse and rabbit models and found that DKK3 altered the atherosclerotic plaque content via increasing SMC numbers and reducing vascular inflammation.

CONCLUSIONS:

Cumulatively, we provide the first evidence that DKK3 is a potent SMC differentiation factor, which might have a therapeutic effect in reducing intraplaque hemorrhage related to atherosclerotic plaque phenotype.

• Authors: Eirini Karamariti, Chungang Zhai, Baoqi Yu, Lei Qiao, Zhihong Wang, Claire M F Potter, Mei Mei Wong, Russell M L Simpson, Zhongyi Zhang, Xiaocong Wang, Ivan Del Barco Barrantes, Christof Niehrs, Deling Kong, Qiang Zhao, Yun Zhang, Yanhua Hu, Cheng Zhang, Qingbo Xu
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 38 Issue 2 Pg. 425-437 (02 2018) ISSN: 1524-4636 [Electronic] United States
• PMID: 29284609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors.

Chemical References

• ATF6 protein, human
• Activating Transcription Factor 6
• Adaptor Proteins, Signal Transducing
• Ataxin-1
• Atxn1 protein, mouse
• Chemokines
• DKK3 protein, human
• Dkk3 protein, mouse
• Intercellular Signaling Peptides and Proteins
• TGFB1 protein, human
• Transforming Growth Factor beta1

Topics

• Activating Transcription Factor 6 (genetics, metabolism)
• Adaptor Proteins, Signal Transducing
• Animals
• Aorta (metabolism, pathology)
• Aortic Diseases (genetics, metabolism, pathology)
• Ataxin-1 (metabolism)
• Atherosclerosis (genetics, metabolism, pathology)
• Carotid Arteries (metabolism, pathology)
• Carotid Stenosis (genetics, metabolism, pathology)
• Cell Transdifferentiation
• Cells, Cultured
• Chemokines
• Disease Models, Animal
• Female
• Fibroblasts (metabolism, pathology)
• Hemorrhage (genetics, metabolism, pathology, prevention & control)
• Humans
• Intercellular Signaling Peptides and Proteins (deficiency, genetics, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout, ApoE
• Muscle, Smooth, Vascular (metabolism, pathology)
• Myocytes, Smooth Muscle (metabolism, pathology)
• Phenotype
• Plaque, Atherosclerotic
• Rabbits
• Stem Cells (metabolism, pathology)
• Transforming Growth Factor beta1 (metabolism)
• Wnt Signaling Pathway