DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells
DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells
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DKK3 (Dickkopf 3) 改变涉及血管祖细胞和成纤维细胞分化为平滑肌细胞的动脉粥样硬化斑块表型
DOI：
10.1161/atvbaha.117.310079
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发表时间：
2018-02-01
影响因子：
8.7
通讯作者：
Xu, Qingbo
中科院分区：
文献类型：
--
作者：
Karamariti, Eirini;Zhai, Chungang;Xu, Qingbo
目的 DKK3 (dickkopf 3) 是一种 36 kD 的分泌糖蛋白，已被证明参与部分重编程细胞和胚胎干细胞向平滑肌细胞 (SMC) 的分化，但对其与血管疾病的关系知之甚少。本研究旨在评估DKK3对动脉粥样硬化斑块组成的影响。 方法和结果在本研究中，我们使用小鼠动脉粥样硬化模型（ApoE（-/-））与DKK3（-/-）联合进行颈动脉串联狭窄，以评估动脉粥样硬化斑块的发展。我们发现，DKK3 的缺失会导致易损的动脉粥样硬化斑块，因为 SMC 数量减少，基质蛋白沉积减少，以及出血和巨噬细胞浸润增加。进一步的体外研究表明，DKK3可以通过激活TGF-β（转化生长因子-β）/ATF6（激活转录因子6）和Wnt信号通路，诱导Sca1（+）（干细胞抗原1）血管祖细胞和成纤维细胞分化为SMC。最后，我们评估了 DKK3 在小鼠和兔模型中的治疗潜力，发现 DKK3 通过增加 SMC 数量和减少血管炎症来改变动脉粥样硬化斑块含量。 结论 总的来说，我们提供了第一个证据表明 DKK3 是一种有效的 SMC 分化因子，可能对减少与动脉粥样硬化斑块相关的斑块内出血具有治疗作用 表型。
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-beta (transforming growth factor-beta)/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.