1. DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells.
- Author
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Karamariti E, Zhai C, Yu B, Qiao L, Wang Z, Potter CMF, Wong MM, Simpson RML, Zhang Z, Wang X, Del Barco Barrantes I, Niehrs C, Kong D, Zhao Q, Zhang Y, Hu Y, Zhang C, and Xu Q
- Subjects
- Activating Transcription Factor 6 genetics, Activating Transcription Factor 6 metabolism, Adaptor Proteins, Signal Transducing, Animals, Aorta metabolism, Aorta pathology, Aortic Diseases genetics, Aortic Diseases pathology, Ataxin-1 metabolism, Atherosclerosis genetics, Atherosclerosis pathology, Carotid Arteries metabolism, Carotid Arteries pathology, Carotid Stenosis genetics, Carotid Stenosis pathology, Cells, Cultured, Chemokines, Disease Models, Animal, Female, Fibroblasts pathology, Hemorrhage genetics, Hemorrhage metabolism, Hemorrhage pathology, Hemorrhage prevention & control, Humans, Intercellular Signaling Peptides and Proteins deficiency, Intercellular Signaling Peptides and Proteins genetics, Male, Mice, Inbred C57BL, Mice, Knockout, ApoE, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle pathology, Phenotype, Rabbits, Stem Cells pathology, Transforming Growth Factor beta1 metabolism, Wnt Signaling Pathway, Aortic Diseases metabolism, Atherosclerosis metabolism, Carotid Stenosis metabolism, Cell Transdifferentiation, Fibroblasts metabolism, Intercellular Signaling Peptides and Proteins metabolism, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, Plaque, Atherosclerotic, Stem Cells metabolism
- 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., (© 2017 The Authors.)- Published
- 2018
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