Dickkopf‐1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1

Abstract

Vascular smooth muscle cells (VSMCs) are considered to be a crucial source of foam cells in atherosclerosis due to their low expression level of cholesterol exporter ATP‐binding cassette transporter A1 (ABCA1) intrinsically. While the definite regulatory mechanisms are complicated and have not yet been fully elucidated, we previously reported that Dickkopf‐1 (DKK1) mediates endothelial cell (EC) dysfunction, thereby aggravating atherosclerosis. However, the role of smooth muscle cell (SMC) DKK1 in atherosclerosis and foam cell formation remains unknown. In this study, we established SMC‐specific DKK1‐knockout (DKK1SMKO) mice by crossbreeding DKK1flox/flox mice with TAGLN‐Cre mice. Then, DKK1SMKO mice were crossed with APOE−/− mice to generate DKK1SMKO/APOE−/− mice, which exhibited milder atherosclerotic burden and fewer SMC foam cells. In vitro loss‐ and gain‐of‐function studies of DKK1 in primary human aortic smooth muscle cells (HASMCs) have proven that DKK1 prevented oxidized lipid‐induced ABCA1 upregulation and cholesterol efflux and promoted SMC foam cell formation. Mechanistically, RNA‐sequencing (RNA‐seq) analysis of HASMCs as well as chromatin immunoprecipitation (ChIP) experiments showed that DKK1 mediates the binding of transcription factor CCAAT/enhancer‐binding protein delta (C/EBPδ) to the promoter of cytochrome P450 epoxygenase 4A11 (CYP4A11) to regulate its expression. In addition, CYP4A11 as well as its metabolite 20‐HETE‐promoted activation of transcription factor sterol regulatory element‐binding protein 2 (SREBP2) mediated the DKK1 regulation of ABCA1 in SMC. Furthermore, HET0016, the antagonist of CYP4A11, has also shown an alleviating effect on atherosclerosis. In conclusion, our results demonstrate that DKK1 promotes SMC foam cell formation during atherosclerosis via a reduction in CYP4A11‐20‐HETE/SREBP2‐mediated ABCA1 expression.

Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases

“…226 Recently, a study has shown that CYP4A11-derived 20-HETE promotes SMC foam cell formation by regulating SREBP2 activation. 96 Studies have shown that CYP synthase-derived EETs or the overexpression of CYP2J2 significantly inhibit leukocyte recruitment and endothelium-leukocyte interactions in the vascular intima by inhibiting the NF-κB pathway. 97 Further mechanistic studies have shown that EETs in endothelial cells reduce the response of NF-κB to inflammatory factor stimulation by inhibiting the degradation of IκB and preventing the vascular wall adhesion of leukocytes.…”