Journal Article

Dickkopf1 destabilizes atherosclerotic plaques and promotes plaque formation by inducing apoptosis of endothelial cells through activation of ER stress

Liu, Xinxin, Chen, Weijia, Zhang, Yu, Di, Mingxue, Li, Mengmeng, Wang, Lin, Zeng, Renya, Zhang, Mei, Wang, Han, Chen, Yifei, Zhang, Yun

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/109 / 13/31 / 13/51 / 13/89 / 14/34 / 631/443/592/75/593/2100 / 631/80/642/1463 / 631/80/82/23 / 631/80/86/2366 / 64/60 / 82/29 / Animals / Antibodies / Aorta - metabolism / Aorta - pathology / Apolipoprotein E / Apolipoproteins E - deficiency / Apolipoproteins E - genetics / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Arteriosclerosis / Atherogenesis / Atherosclerosis / bcl-2-Associated X Protein - metabolism / Biochemistry / Biomedical and Life Sciences / Caspase 3 - metabolism / Cell Biology / Cell Culture / Cytokines - metabolism / Dkk1 protein / Endoplasmic reticulum / Endoplasmic Reticulum Stress - drug effects / Endoplasmic Reticulum Stress - genetics / Endothelial cells / Human Umbilical Vein Endothelial Cells / Humans / Immunology / Intercellular Signaling Peptides and Proteins - chemistry / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / JNK protein / Life Sciences / Lipoproteins, LDL - pharmacology / Low density lipoprotein / Mice / Original / original-article / Pathogenesis / Phenylbutyrates - pharmacology / Plaque, Atherosclerotic - metabolism / Plaque, Atherosclerotic - pathology / Plaques / Plasma levels / Proto-Oncogene Proteins c-bcl-2 - metabolism / RNA Interference / Sialomucins - metabolism / Signal transduction / Signal Transduction - drug effects / Transcription Factor CHOP - metabolism / Umbilical vein / Up-Regulation - drug effects / Wnt protein