Dickkopf1 destabilizes atherosclerotic plaques and promotes plaque formation by inducing apoptosis of endothelial cells through activation of ER stress.
Dickkopf1 destabilizes atherosclerotic plaques and promotes plaque formation by inducing apoptosis of endothelial cells through activation of ER stress.
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Dickkopf1 通过激活 ER 应激诱导内皮细胞凋亡，从而破坏动脉粥样硬化斑块的稳定性并促进斑块形成
DOI：
10.1038/cddis.2017.277
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发表时间：
2017-07-13
影响因子：
9
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Di M;Wang L;Li M;Zhang Y;Liu X;Zeng R;Wang H;Chen Y;Chen W;Zhang Y;Zhang M
多项临床研究报道Dickkopf1 （DKK1）血浆水平与动脉粥样硬化相关。然而，DKK1对动脉粥样硬化斑块形成和易损性的影响尚不清楚。本研究通过靶向内皮细胞和评估可能的细胞机制来研究DKK1对斑块扩大和不稳定的影响。DKK1对ApoE−/−小鼠动脉粥样硬化和斑块稳定性的影响，使用慢病毒注射来敲低和敲入DKK1基因。DKK1的存在导致动脉粥样硬化病变扩大和不稳定，细胞凋亡增加，而在动脉粥样硬化的整个过程中，DKK1的沉默减轻了斑块的形成和易感性。人脐静脉内皮细胞（HUVEC）在ox-LDL处理下，DKK1表达呈时间和浓度依赖性上调。DKK1的干扰可逆转ox- ldl诱导的huvec细胞凋亡。这种作用的机制是DKK1激活JNK信号转导途径并抑制典型Wnt信号转导，随后激活IRE1α和eif2α/CHOP途径。综上所述，DKK1促进斑块形成和易损性部分是通过诱导内皮细胞凋亡，部分是通过诱导jnk -内质网应激通路和抑制典型Wnt信号传导。
Several clinical studies reported that Dickkopf1 (DKK1) plasma levels are correlated with atherosclerosis. However, the impact of DKK1 on the formation and vulnerability of atherosclerotic plaques remains elusive. This study investigated DKK1’s effects on enlargement and destabilization of plaques by targeting endothelial cells and assessing the possible cellular mechanisms involved. The effects of DKK1 on atherogenesis and plaque stability were evaluated in ApoE−/− mice using lentivirus injections to knockdown and knock-in the DKK1 gene. The presence of DKK1 resulted in enlarged and destabilized atherosclerotic lesions and increased apoptosis, while silencing of DKK1 alleviated plaque formation and vulnerability in the whole progression of atherosclerosis. DKK1 expression was upregulated in response to ox-LDL treatment in a time- and concentration-dependent manner on human umbilical vein endothelial cell (HUVEC). The interference of DKK1 reversed ox-LDL-induced apoptosis in HUVECs. The mechanism underlying this effect was DKK1’s activation of the JNK signal transduction pathway and inhibition of canonical Wnt signaling, following by activation of the IRE1α and eif2α/CHOP pathways. In conclusion, DKK1 promotes plaque formation and vulnerability partly by inducing apoptosis in endothelial cells, which partly through inducing the JNK-endoplasmic reticulum stress pathway and inhibiting canonical Wnt signaling.
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影响因子：
5.6
作者：
Chen S;Li N;Deb-Chatterji M;Dong Q;Kielstein JT;Weissenborn K;Worthmann H
通讯作者：
Worthmann H
影响因子：
37.8
作者：
Ehara, S;Ueda, M;Becker, AE
通讯作者：
Becker, AE
影响因子：
6.4
作者：
Hirata, Hiroshi;Hinoda, Yuji;Dahiya, Rajvir
通讯作者：
Dahiya, Rajvir
影响因子：
7.7
作者：
Gustafson B;Smith U
通讯作者：
Smith U
影响因子：
9
作者：
Kushwaha P;Khedgikar V;Gautam J;Dixit P;Chillara R;Verma A;Thakur R;Mishra DP;Singh D;Maurya R;Chattopadhyay N;Mishra PR;Trivedi R
通讯作者：
Trivedi R