Dickkopf-1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1
Dickkopf-1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1
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DOI：
10.1096/fj.202300295r
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发表时间：
2023-08-01
期刊：
影响因子：
4.8
通讯作者：
Zhang，Mei
中科院分区：
文献类型：
--
作者：
Li，Xiao;Zheng，Tengfei;Zhang，Mei
血管平滑肌细胞（VSMC）由于其胆固醇输出蛋白ATP结合盒转运蛋白A1（ABCA1）的低表达水平而被认为是动脉粥样硬化中泡沫细胞的重要来源。虽然明确的调节机制很复杂，尚未完全阐明，但我们之前报道过Dickkopf-1（DKK 1）介导内皮细胞（EC）功能障碍，从而加剧动脉粥样硬化。然而，平滑肌细胞（SMC）DKK 1在动脉粥样硬化和泡沫细胞形成中的作用仍不清楚。在这项研究中，我们通过将DKK 1flox/plant小鼠与TAGLN ‐ Cre小鼠杂交建立了SMC特异性DKK 1基因敲除（DKK 1SMKO）小鼠。然后，将DKK 1SMKO小鼠与APOE −/−小鼠杂交以产生DKK 1SMKO/APOE −/−小鼠，其表现出较轻的动脉粥样硬化负荷和较少的SMC泡沫细胞。DKK 1在原代人主动脉平滑肌细胞（HASMC）中的体外功能丧失和获得研究证明，DKK 1可阻止氧化脂质诱导的ABCA 1上调和胆固醇流出，并促进SMC泡沫细胞形成。HASMCs的RNA测序（RNA-seq）分析以及染色质免疫沉淀（ChIP）实验表明，DKK 1介导转录因子CCAAT/增强子结合蛋白δ（C/EBP δ）与细胞色素P450表氧化酶4A11（CYP4A11）启动子的结合，以调节其表达。此外，CYP4A11及其代谢产物20-HETE-促进转录因子固醇调节元件结合蛋白2（SREBP 2）的活化，介导SMC中ABCA 1的DKK 1调节。此外，CYP4A11拮抗剂HET0016也显示出对动脉粥样硬化的缓解作用。总之，我们的结果表明，DKK 1通过减少CYP4A11 - 20-HETE/SREBP 2-介导的ABCA 1表达促进动脉粥样硬化期间SMC泡沫细胞形成。
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/floxmice with TAGLN‐Cre mice. Then, DKK1SMKOmice 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.