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

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

doi:10.1038/cddis.2017.277

Abstract

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.

Highlights

Recent studies have found that acute coronary syndrome (ACS) is associated with both the sudden rupture of atherosclerotic plaques and the rapid development of these plaques
We investigated the effect of modulated DKK1 expression on atherosclerosis plaques in ApoE − / − mice and EC apoptosis; and explored the underlying mechanisms in endothelial cells using human umbilical vein endothelial cells (HUVECs)
Endomucin is a marker for endothelial cells,[14] and MOMA-2 is a marker for monocyte-macrophage.[15]

Summary

Introduction

Recent studies have found that acute coronary syndrome (ACS) is associated with both the sudden rupture of atherosclerotic plaques and the rapid development of these plaques. Received 30.11.16; revised 10.4.17; accepted 13.4.17; Edited by A Oberst enhancer-binding protein-homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), and the presence of atherosclerotic plaques in human coronary artery lesions, suggesting that ERS is involved in the development of plaque instability in humans.[12] Disrupting the secretion of Wnt5a, a Wnt pathway agonist, has been shown to induce ERS in mammalian cells, indicating that a correlation exists between Wnt secretion and ERS.[13] DKK1 is an important regulator of the Wnt pathway,[8] yet, its role in ERS-associated apoptosis in atherosclerosis remains unclear. We investigated the effect of modulated DKK1 expression on atherosclerosis plaques in ApoE − / − mice and EC apoptosis; and explored the underlying mechanisms in endothelial cells using human umbilical vein endothelial cells (HUVECs)

Methods

Results

Conclusion