Dickkopf-1通过CYP4A11/SREBP2/ABCA1促进了血管光滑肌细胞泡细胞的形成和动脉样硬化发展
Xiao Li1, Tengfei Zheng1, Yu Zhang1
1National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
概括
Dickkopf-1 (DKK1) 通过降低胆固醇输出者ABCA1的表达,促进动脉样硬化中的血管光滑肌细胞泡细胞的形成. 这一途径涉及CYP4A11,20-HETE和SREBP2,突出显示了潜在的治疗点.
科学领域:
- 心血管生物学 心血管生物学
- 分子医学是分子医学.
- 动脉样硬化研究 动脉样硬化研究
背景情况:
- 血管光滑肌细胞 (VSMCs) 导致动脉样硬化中的泡细胞形成,这是由于ATP结合盒载体A1 (ABCA1) 的表达率较低.
- 已知Dickkopf-1 (DKK1) 会导致内皮细胞功能障碍并恶化动脉样硬化.
- DKK1在VSMC和泡细胞发育中的特定作用以前未被定义.
研究的目的:
- 研究DKK1在平滑肌细胞 (SMC) 中对动脉样硬化和泡细胞形成的作用.
- 阐明DKK1在SMC中影响ABCA1表达和胆固醇平衡的分子机制.
主要方法:
- 生产特定于SMC的DKK1-knockout (DKK1SMKO) 小鼠,并随后与APOE-/-小鼠进行交叉.
- 使用初级人类大动脉光滑肌细胞 (HASMCs) 的体外研究与DKK1功能损失和增益实验.
- RNA测序 (RNA-seq) 和染色体免疫沉 (ChIP) 测试以确定分子点和途径.
主要成果:
- DKK1SMKO/APOE/-小鼠的动脉样硬化负担降低,SMC泡细胞减少.
- 在HASMC中,DKK1抑制了氧化脂质诱导的ABCA1上调和胆固醇排放,促进泡细胞的形成.
- DKK1通过C/EBPδ结合来调节CYP4A11的表达,而CYP4A11-20-HETE/SREBP2通路调节DKK1对ABCA1.1的影响.
结论:
- 在动脉样硬化中,DKK1促进SMC泡细胞的形成.
- 该机制涉及DKK1介导的CYP4A11-20-HETE/SREBP2信号的下调,导致ABCA1的表达减少.
- 向CYP4A11途径可能为动脉样硬化提供治疗策略.
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